Prioritization of Molecular Targets for Antimalarial Drug Discovery
- Barbara ForteBarbara ForteWellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, DD1 5EH, United KingdomMore by Barbara Forte
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- Sabine OttilieSabine OttilieDepartment of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, United StatesMore by Sabine Ottilie
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- Andrew PlaterAndrew PlaterWellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, DD1 5EH, United KingdomMore by Andrew Plater
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- Brice Campo
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- Koen J. DecheringKoen J. DecheringTropIQ Health Sciences, 6534 AT, Nijmegen, The NetherlandsMore by Koen J. Dechering
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- Francisco Javier GamoFrancisco Javier GamoGlobal Health, GSK, 28760-Tres Cantos, Madrid, SpainMore by Francisco Javier Gamo
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- Daniel E. GoldbergDaniel E. GoldbergDivision of Infectious Diseases, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United StatesMore by Daniel E. Goldberg
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- Eva S. IstvanEva S. IstvanDivision of Infectious Diseases, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United StatesMore by Eva S. Istvan
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- Marcus LeeMarcus LeeWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, United KingdomMore by Marcus Lee
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- Amanda K. LukensAmanda K. LukensInfectious Disease and Microbiome Program, Broad Institute, Cambridge, Massachusetts 02142, United StatesDepartment of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, United StatesMore by Amanda K. Lukens
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- Case W. McNamaraCase W. McNamaraCalibr, a Division of The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, California 92037, United StatesMore by Case W. McNamara
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- Jacquin C. NilesJacquin C. NilesDepartment of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge Massachusetts 02139-4307, United StatesMore by Jacquin C. Niles
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- John OkomboJohn OkomboDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United StatesMore by John Okombo
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- Charisse Flerida A. PasajeCharisse Flerida A. PasajeDepartment of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge Massachusetts 02139-4307, United StatesMore by Charisse Flerida A. Pasaje
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- Miles G. Siegel
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- Dyann WirthDyann WirthInfectious Disease and Microbiome Program, Broad Institute, Cambridge, Massachusetts 02142, United StatesDepartment of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, United StatesMore by Dyann Wirth
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- Susan WyllieSusan WyllieWellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, DD1 5EH, United KingdomMore by Susan Wyllie
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- David A. FidockDavid A. FidockDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United StatesDivision of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United StatesMore by David A. Fidock
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- Beatriz Baragaña*Beatriz Baragaña*E-mail: [email protected]Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, DD1 5EH, United KingdomMore by Beatriz Baragaña
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- Elizabeth A. Winzeler*Elizabeth A. Winzeler*E-mail: [email protected]Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, United StatesMore by Elizabeth A. Winzeler
- , and
- Ian H. Gilbert*Ian H. Gilbert*E-mail: [email protected]Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, DD1 5EH, United KingdomMore by Ian H. Gilbert
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Abstract
There is a shift in antimalarial drug discovery from phenotypic screening toward target-based approaches, as more potential drug targets are being validated in Plasmodium species. Given the high attrition rate and high cost of drug discovery, it is important to select the targets most likely to deliver progressible drug candidates. In this paper, we describe the criteria that we consider important for selecting targets for antimalarial drug discovery. We describe the analysis of a number of drug targets in the Malaria Drug Accelerator (MalDA) pipeline, which has allowed us to prioritize targets that are ready to enter the drug discovery process. This selection process has also highlighted where additional data are required to inform target progression or deprioritization of other targets. Finally, we comment on how additional drug targets may be identified.
This publication is licensed under
CC-BY 4.0.
License Summary*
You are free to share (copy and redistribute) this article in any medium or format and to adapt (remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
License Summary*
You are free to share (copy and redistribute) this article in any medium or format and to adapt (remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
License Summary*
You are free to share (copy and redistribute) this article in any medium or format and to adapt (remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
KEYWORDS:
Malaria is caused by Anopheles mosquito-transmitted protozoan Plasmodium parasites. Five species of Plasmodium parasites cause human disease: Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Of these, P. falciparum is associated with the most deaths, although infections due to P. vivax and P. knowlesi can cause severe disease. Infection with P. vivax and P. ovale is associated with dormant liver-stage forms (hypnozoites) that can be activated months to years after the primary infection, leading to relapse and recurring disease.
Malaria remains a major threat to human health, imposing a heavy social and economic burden, particularly for people from low- and middle-income countries. An estimated 229 million new cases occurred in 2019, predominantly in sub-Saharan Africa, South America, and Asia, resulting in an estimated 409 000 deaths. (1) Children under five and pregnant women are at higher risk of suffering from severe malaria that can lead to death.
According to the WHO 2020 report on malaria, annual mortality decreased by 60% over the period 2000 to 2019, an unprecedented level of success that saved an estimated 7.6 million lives. However, despite the considerable progress made, these gains have plateaued since 2015 and the Global Technical Strategy (GTS) goals for reductions of at least 40% compared to 2015 in both disease and death by 2020 have been missed. (1) Since 2000, a variety of interventions have helped to drive this progress, including the use of more extensive vector control measures, reliable diagnostic tests, and improved drug therapy. However, continued progress is hampered by the emergence of mosquitoes resistant to current insecticides and parasites resistant to currently used antimalarial drugs, especially in the Greater Mekong Subregion. (2) Thus, continued investment in research and development is needed to develop the tools required to stay ahead of resistance and generate the progress needed to achieve the GTS goals.
History has demonstrated that P. falciparum resistance to widely used antimalarials inevitably emerges, limiting their effectiveness. There is established resistance or partial resistance to nearly all currently registered antimalarial drugs (with the exceptions of lumefantrine and pyronaridine), and the need for new drugs working through differentiated modes of action is urgent. The emergence of resistance can be delayed by combining antimalarials with different modes of action. Therefore, the identification of new, validated drug targets is crucial in developing novel antimalarials capable of treating parasite populations resistant to current therapies.
The challenge is to identify new treatments that are well-tolerated in vulnerable populations, such as pregnant women, children under 5, and people suffering from malnutrition or coinfection with other pathogens. Another challenge is how best to treat people with asymptomatic malaria and protect vulnerable populations in endemic regions from becoming symptomatic. (3) To guide the discovery of new treatments that tackle these challenges, clear Target Product Profiles (TPP; descriptions of medicines) are required. These are then used to derive Target Candidate Profiles (TCP; descriptions of molecules) to guide the antimalarial drug discovery and development process. In 2017, Medicines for Malaria Venture (MMV), in discussions with the wider malaria community, updated the TCPs (Table 1) and TPPs (Table 2) (4) defined first in 2013, (5) taking into account the learnings and insights gained in recent years. With the goal of eradicating and not just controlling malaria, the new drug pipeline should contain, in addition to compounds efficacious enough to treat symptomatic malaria, drugs able to (1) interrupt disease transmission; (2) prevent relapsing malaria, due to hypnozoites; (6,7) (3) protect the most vulnerable patients from getting disease; and (4) clear the malaria burden by treating asymptomatic cases of malaria.
Table 1. Target Candidate Profile (TCP) definitions
| TCP | Goal | Definition |
|---|---|---|
| TCP-1 | Treatment of disease (both severe and uncomplicated) and chemoprophylaxis (protecting vulnerable populations) | Compounds active against the asexual blood stage of the Plasmodium life cycle and active against all resistant strains |
| TCP-3 | Anti-relapse (treatment for recurrent malaria) | Compounds active against liver stage hypnozoites |
| TCP-4 | Prophylaxis (for migratory population or outbreak prevention) | Compounds active against liver stages (ideally providing protection for at least a month) |
| TCP-5 | Transmission blockers (prevention strategies, e.g., treatment of asymptomatic infection) | Compounds active against parasite gametocytes |
| TCP-6 | Transmission blockers | Compounds that block transmission by targeting the insect vector (mosquitocides / endectocides) |
Table 2. Target Product Profile (TPP) definitions
| TPP | Goal | Definition |
|---|---|---|
| TPP-1 | Treating active disease | Ideally, a combination of TCP-1 with TCP-5 or TCP-3 in order to cure acute or uncomplicated malaria in both adults and children, ideally given as a single oral dose. A fast-killing TCP-1 compound with parenteral administration is essential for severe malaria. |
| TPP-2 | Chemoprotection | Ideally a combination of TCP-4 and TCP-1 (for emerging infection) with the goal to treat migratory populations or prevent outbreaks. |
Phenotypic screening platforms focusing on different life cycle stages of the parasite have been developed that can identify hits with antimalarial activity. (8−12) Targets associated with phenotypic hits are rarely identified during the early stages of drug discovery, which could prove a challenge to the downstream development and optimization of these compounds. Target-based drug discovery can offer several advantages over traditional phenotypic screening:
• The ability to develop target-specific biochemical assays, allowing the identification of chemical start points of insufficient potency to be found in a phenotypic screen.
• The possibility for alternative hit generation approaches such as fragment and structure-based methods, virtual screening, or screening of DNA-encoded libraries (DEL). (13)
• Utilization of structural information to design selectivity against the human orthologue, when present.
• Facilitate scaffold hopping, in the event of pharmacokinetic or toxicological issues associated with a particular chemical series.
• Structure-based approaches have also been used to develop compounds with reduced potential for resistance to emerge. (14)
• Knowledge of the target is also important in designing combination treatments.
• Knowledge of the target is useful in monitoring for resistance development during clinical trials and following deployment.
MalDA (Malaria Drug Accelerator) is an international consortium of 17 groups funded by the Bill & Melinda Gates Foundation. The goal of MalDA is to identify novel drug targets in Plasmodium, primarily by linking active compounds to molecular targets through comprehensive mode of action studies. (15) More recently, the consortium’s mission has expanded to include the development of target-specific assays, hit discovery, and compound progression to early lead status. The early lead criteria that we are adopting are those defined by MMV. This is presented on their Web site (www.mmv.org). MalDA members are summarized in Figure 1.
Figure 1
Figure 1. Geographical location of MalDA consortium members. MalDA, with its state-of-the-art Plasmodium-adapted technology platforms in bioinformatics, chemo-informatics, chemo-proteomics, genetic manipulation, metabolomics, in vivo resistance evaluation, and medicinal chemistry expertise, is at the forefront of the antimalarial drug discovery process by providing tools to accelerate the finding of new starting points for drug discovery (www.malariaDA.org). (15)
How Are Tractable Drug Targets Identified?
ARTICLE SECTIONS
Tractable antimalarial targets can be identified from several different sources. First, they can be found by establishing the molecular targets of phenotypic screening hits of in vitro cultured P. falciparum asexual blood stage parasites. Target deconvolution is carried out using a variety of approaches. The principal route has involved in vitro resistance generation followed by whole-genome sequencing or previously by whole-genome microarray analysis. (15,16) This strategy has proven highly successful in identifying the molecular targets of many, but not all, phenotypically active compounds. (17−19) The location of the mutations can give indications as to whether and where the compound binds to the protein. Indeed, this approach can provide important additional information such as identifying and understanding mechanisms of resistance associated with the target. While mechanisms of resistance can give indications of the mode of action, they can also occur in general resistance mechanisms, such as efflux pumps or other modulators of drug potency.
Additional techniques are now being utilized to identify the mechanisms of action of phenotypic actives, which are particularly valuable when resistant parasites cannot be selected. One of these, Thermal Proteome Profiling, (20) is a mass-spectrometry-facilitated approach that exploits the biophysical principle that binding of a ligand induces thermal stabilization of target proteins. Shifts in the thermal stability of proteins within the parasite proteome are monitored in the presence and absence of drug to identify putative targets. Another technique, metabolomics, is used to give a broad indication of metabolic pathways affected by drug action and provides metabolic fingerprints of compounds acting via previously defined modes of action. (16)
Once the target(s) of phenotypic hits is(are) identified by these primary methodologies, secondary experiments are required to validate this(these) putative target(s). Despite the increasingly sophisticated battery of techniques available to identify molecular targets, there are still compounds where the target or mode of action has yet to be established. This may be due to factors such as compounds working through polypharmacology or targeting host proteins or targets for which it is really difficult to raise resistance. Additionally, some compounds also act via interaction with nonprotein targets, which can be challenging to deconvolute.
Several targets with potential to be exploited for drug discovery have also been suggested by literature precedent, or through general precedence as drug targets in other disease areas. Currently, there is considerable interest in amino acyl tRNA synthetases as potential antimalarial targets. These enzymes have been established as viable drug targets in a number of different pathogens. Interestingly, a number of these enzymes have been found to be the target of phenotypic hits in Plasmodium using target deconvolution methods described above. (21−23) Literature-based targets, however, need careful scrutiny since there can be a disconnect between activity against a molecular target in a biochemical assay and activity in cellular and animal models of disease. (24) Indeed, the failure of biochemical/enzymatic hits to translate to growth inhibition and cytocidal activity against the parasite has been a confounding factor in the identification of lead compounds, not only for antimalarials but for antimicrobials in general.
Finally, fundamental research by the malaria research community, both within and outside MalDA, has led to the identification of numerous potential drug targets. Once again, targets identified via this route require careful assessment prior to embarking on expensive and time-consuming drug discovery programs.
Overview of Requirements for a Drug Target
ARTICLE SECTIONS
When pursuing a target prioritization program, it is important to identify the key requirements for a drug target. We (25−28) and others (29) have published articles in this area. The target must be essential for the progression or pathophysiology of the disease; in the case of Plasmodium, this equates to survival or transmission of the parasite. The target also needs to be druggable: its function needs to be modifiable by a small molecule or biologic. In the case of malaria, this must be an orally available small molecule, to meet the criterion of a low cost of goods. Another important concept is target vulnerability; this is how much and for how long it is necessary to modulate the activity of the target to have the desired phenotypic effect. It is very challenging to maintain high levels of pharmacological inhibition of a target for prolonged periods of time; therefore, targets requiring relatively low levels of inhibition and/or a short duration of action to quickly “tip” the parasites to death are more attractive. Genetic approaches to engineer the conditional knockdown of a desired target are important here. (30,31) Further, in the case of malaria, the rate of parasite kill is vitally important, since patients with malaria can rapidly become severely ill and die. Therefore, targets that require inhibition for prolonged periods to kill a parasite should not be pursued to treat asexual blood stage infections. For prophylaxis or transmission blocking, a slower rate of kill may be acceptable.
Another important consideration is the emergence of drug resistance, which is a major concern for anti-infectives, including antimalarials. A target with low resistance propensity, or no obvious bypass mechanism, is preferable. However, understanding resistance mechanisms could lead to alternate treatments (e.g., combination therapy) or attempts to redesign compounds, for example to mitigate the impact of a commonly occurring resistance mutation. (32) Analysis of existing polymorphisms (using genomic databases of thousands of patient isolates) could also be a consideration. A high level of polymorphism could be indicative of higher flexibility to accumulate protein changes and thus an increased propensity to select resistance.
Selectivity is also a requirement, aiming to minimize off-target liabilities that might cause drug candidates to fail later in development. For malaria, compounds should selectively modulate the parasite target over the host equivalent, unless there is a biological reason why inhibition of the host equivalent does not lead to toxicological consequences. The latter is very difficult to predict however. Since most drug discovery paradigms use some form of screening (usually high-throughput) to identify chemical starting points, there also needs to be a route to develop an appropriate assay for a drug target. While not considered a prerequisite for choosing a target, having access to structural information can be a major benefit, as described above.
Some requirements are specific to malaria and must be met for a particular target to be viable (see Table 1). For example, several species of Plasmodium cause malaria, and having a target that is conserved in these species enhances the likelihood that a single treatment can be developed. There are also different life cycle stages for the parasite, so having a compound that can act at multiple stages is desirable.
Process for Target Prioritization
ARTICLE SECTIONS
MalDA has a large portfolio of potential drug targets. We decided to carry out a target prioritization process for several reasons: (1) to identify targets that have the potential to progress into drug discovery programs; (2) to identify targets lacking key information or validation required for progression; (3) to efficiently prioritize future work; and (4) to disseminate our assessment of targets more broadly to the malaria drug discovery community. To facilitate this process, we have generated “target cards” where the information for each criterion is stored in summary form for each of the targets.
We designed a two-tier cascade, associated with a ranking system to assess and prioritize targets (Table 3) based on previously published concepts. (25−29) In tier 1, the level of genetic and chemical validation and the potential to develop resistance were evaluated, while tier 2 encompassed druggability, TCP fit, toxicity, novelty/prior information, assay readiness and structural information. The scoring system, while not perfect, is a way of highlighting high-priority targets. Certain criteria are stop/go decision points. For example, a target that is not essential or does not fulfill one specific TPP/TCP should not progress into drug discovery.
Table 3. Criteria for Target Prioritization
| tier 1 target assessment | ranking | |
|---|---|---|
| Genetic validation | Conditional knockout. Target vulnerability upon conditional knock-down | high |
| Essential in genome-wide saturation mutagenesis in P. falciparum and/or homologous recombination-mediated knockout screen in P. berghei | medium | |
| Chemical validation | Compound-target pair established rigorously | high |
| Good correlation between enzyme and cell activity over 3 log units for a compound series | medium | |
| Resistance potential | Irresistible—no resistance found in selections | high |
| MIR 8–9 and no cross resistance with any drug in clinical use or development | medium | |
| 6 < MIR < 8 and no cross resistance with any drug in clinical use or development | low | |
| MIR ≤ 6 and an EC50 shift > 10-fold; or evidence of high-grade resistance-conferring SNPs in field isolates; or enzyme not conserved across Plasmodium species | STOP | |
| tier 2 target assessment | score | |
|---|---|---|
| Druggability | Identification of small molecule inhibitors with drug-like physicochemical properties | high |
| Computational analysis of the crystal structure or a high quality homology model | medium | |
| TPP/TCP fit | Must be active against at least two life cycle stages at similar concentrations OR blood stage asexual stages with a fast rate of kill | STOP/GO |
| Toxicity | No close orthologue present; selective small molecule inhibitors for parasite enzyme vs human enzyme | high |
| Novelty/prior information | Previous work has indicated issues with chemistry, but potential way forward using new information/chemistry | medium |
| Previous work has indicated that drug-like inhibitors with in vivo activity can be generated and compound(s) in late stage development; potential for back up compound. | low | |
| Assay readiness | Protein expressed and biochemical assay developed for this protein or a close orthologue | high |
| No P. falciparum protein expressed, but (evidence for) assay for orthologue or reporter cell assay developed | medium | |
| Structural information | Structure of target protein and cocrystal structures with ligands; evidence that it can be soaked | high |
| Structure of target protein, but no complex; close orthologue with structures; potential for chimeras | medium | |
Tier 1
We considered three different genetic validation methods to determine the essentiality of a Plasmodium gene. First, the genome-wide saturation mutagenesis screen in P. falciparum asexual blood stages identified likely dispensable and essential genes through mutagenesis index scores (MIS) and mutagenesis fitness scores (MFS). (33) Second, homologous recombination-mediated knockout screens in the rodent malaria parasite P. berghei provide additional information on likely essential genes. (34) Finally, validation of the genetic essentiality of some targets of interest was available from conditional knockouts and knockdown experiments carried out mostly by the Niles lab. (30) In this context, conditional knockdowns are of interest to assess target vulnerability, i.e., the duration and extent of reduction of target levels or activity required to compromise parasite viability. In addition, the presence of loss-of-function alleles in the gene in whole-genome sequences from either population studies or in vitro resistance selection experiments were also considered as risks. Molecular targets scored high when the corresponding gene was deemed to be essential by the three methods. A target was considered to have no potential for drug discovery if viable parasites were obtained when the gene was abolished completely in a knockout experiment.
Two different levels of chemical validation are considered in our assessment, with the highest score for chemical validation being given to compound–target pairs that have been rigorously established. Ideally, this should include reduced compound susceptibility of transgenic parasites that encode the mutations selected through drug pressuring studies and evidence of compound inhibition of recombinant enzyme. Targets showing good correlation between recombinant enzyme inhibition and parasite growth inhibition over 3 log units for a compound series were also scored for chemical validation.
The final criterion in tier 1 is the resistance potential. First, targets associated to compounds showing a Minimum Inoculum for Resistance (MIR) > 8 (i.e., requiring a minimum of 108 parasites to generate resistance) are preferable and received the highest score, while those with a MIR ≤ 6 with a >10-fold increase in EC50 were considered high risk and were not recommended for drug discovery projects. (35,36) In addition, the MalariaGen database provides genome variation data on over 7000 P. falciparum genomes, allowing us to search for the number of SNPs, amino acid changes, and known resistance mutations for a gene of interest (www.malariagen.net). (37) Preferably, a target would have a high degree of conservation across field isolates and across multiple Plasmodium species.
Targets scoring well for essentiality, for parasite survival, and with a manageable resistance risk can progress to tier 2 assessment.
Tier 2
Molecular targets with known small molecule inhibitors with drug-like properties (38−40) receive the highest possible score for druggability. In the absence of known inhibitors, computational analysis of the crystal structure or a high-quality homology model can also be used to assess druggability. (41) Some target classes have been extensively investigated in the context of drug discovery in other disease areas and therefore are expected to be druggable, for example, kinases or bromodomains. For targets for which there is prior drug discovery experience, it is important to leverage prior knowledge. For those programs that have been terminated, was this due to a fundamental issue of target biology? Or was the chemical matter inappropriate, and if so, what is the likelihood of overcoming this? If there is a drug discovery program ongoing elsewhere, is there something different that can be added? It is important not to duplicate work, particularly in a resource-limited disease area. However, given the high attrition rate, until a compound has reached clinical proof of concept, backup strategies need to be considered.
The tier 2 assessment includes an evaluation of the potential to develop selective inhibitors for the targets of interest. The absence of a close human orthologue or the presence of known selective inhibitors are the best indicators. When there is a human orthologue and no known selective inhibitors, a promising target should at least show structural evidence that there are exploitable differences in active sites of the parasite and the human orthologue to facilitate selective inhibitor design. It is also possible that there are differences in biology, which may make Plasmodium more sensitive to inhibition of the target than the human host, particularly over the short time scale that is required for treatment of the asexual blood stage infection.
Finally, other issues considered here are TPP/TCP fit, the presence of structural information, and the availability of appropriate assay(s). For those targets where recombinant protein is difficult to produce, phenotypic assays with conditional knockdown parasites can be used to identify chemical starting points, although this may miss weaker or non-cell permeant hits.
In addition to the basic scoring system, we have decided that we need a diverse target portfolio. For example, the amino acid tRNA synthetases are robustly validated drug targets, but it is important to have a degree of diversity in any drug discovery pipeline to mitigate against the possibility of unforeseen scientific developments deprioritizing a specific target or target class. There is also an element of opportunities as well as taking risks with novel targets where there is relatively little information.
Outcome of triaging
ARTICLE SECTIONS
As a result of this target prioritization process, we classified targets as follows:
• High Priority: These are targets that have a high degree of validation and are likely to be good drug targets. There may be missing data that would be required prior to the progression of these targets into a full-scale drug discovery program. However, this is where we think resources should be prioritized, to complete validation experiments and progress them into drug discovery.
• Targets under Consideration: These are targets that look promising, but additional data are required to move them to a stage where they could be prioritized. For example, this might be missing information on TCP fit, or a lack of chemical tools.
• New and Emerging Targets: Targets requiring significant work focused on validation. It is important to highlight specific experiments required to validate/invalidate particular targets.
• Deprioritized Targets: Targets where we do not think resources are justified from a MalDA perspective. Here, there are two separate categories: (1) invalidated targets, or those unlikely to be inhibited by compounds capable of fulfilling one of the MMV TCPs, and (2) those targets where there are already several substantial development programs elsewhere. Examples include PfATP4 (where there are multiple programs ongoing) (18) and plasmepsin X (42) (see Table 4 for further examples).
Table 4. Examples of Deprioritized Targets for MalDA
| target name (abbreviation) | Pf gene ID | reason for deprioritization |
|---|---|---|
| N-myristoyl transferase (NMT) | PF3D7_1412800 | slow killer, challenges with selectivity compared to the human enzyme |
| P-type ATPase 4 (ATP4) | PF3D7_1211900 | multiple series under investigation in the drug discovery pipeline |
| plasmepsin X | PF3D7_0808200 | multiple series under investigation in the drug discovery pipeline |
| Niemann–Pick type C1-related protein (NCR1) | PF3D7_0107500 | resistance risk, slow rate of kill and single-stage efficacy |
| dihydrofolate reductase (DHFR) | PF3D7_0417200 | clinically approved inhibitor; resistant parasites widespread in the field |
| dihydroorotate dehydrogenase (DHODH) | PF3D7_0603300 | multiple chemotypes have been developed, and resistance can arise readily |
| phosphatidyl inositol 4-kinase (PI4K) | PF3D7_0509800 | multiple chemotypes have been developed, and resistance can arise readily |
Inevitably, there is a degree of judgment and subjectivity, as information gaps will exist for most targets, and there are many aspects of Plasmodium biology and host–parasite interactions that are unknown. The ultimate proof of validation of any drug target is a clinical proof of concept, as shown for example with inhibitors of P. falciparum dihydrofolate reductase, dihydroorotate dehydrogenase, the cytochrome bc1 complex, or phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ kinase). (43)
The outcome of our initial triage is shown in Figure 2. This represents the targets that we have had the opportunity to assess. There are other interesting targets that remain to be assessed by our target validation process.
Figure 2
Figure 2. Current MalDA target portfolio
Tables 5 (high-priority targets) and 6 (targets under consideration) illustrate specific details for some of the targets in Figure 2. Target prioritization is a dynamic process—prioritization of individual targets may change as key information becomes available. In Figure 2, we provide our current classification of targets. However, this will change, so we have created a Web site where this information will be updated (www.malariaDA.org). We also invite members of the malaria research community to suggest new targets, add to our assessments, and provide additional information on targets being considered by MalDA.
Table 5. Targets Ranked As High Priority
| target name (abbreviation) | Pf gene ID | key questions | next steps |
|---|---|---|---|
| serine/threonine protein kinase, putative (44) (CLK3) | PF3D7_1114700 | can target be structurally enabled? | optimization of hits; more chemical starting points |
| cGMP-dependent protein kinase (PKG) | PF3D7_1436600 | rate of kill with selective inhibitor | Rate of kill (PRR assay); optimize chemical starting points |
| geranylgeranyl pyrophosphate synthase (F/GGPPS) | Pf3D7_1128400 | small molecule inhibitors | generate additional chemical matter |
| phenylalanine tRNA synthetase–alpha subunit (PheRS) | PF3D7_0109800 | resistance risk | more screening/scaffold hopping to identify more start points |
| prolyl tRNA synthetase, putative (ProRS) | PF3D7_0925300 | is selectivity versus human orthologues possible? | additional screens |
| acetyl CoA synthetase, putative (AcAS) | PF3D7_0627800 | resistance risk; can the target be structurally enabled? | proof of concept from MMV693183 first-in-human study; establish alternate lead series from existing hits/new screens and H2L; crystal structure to guide chemistry program |
| isoleucine—tRNA ligase, putative (cIRS) | PF3D7_1332900 | rate of kill, resistance risk | generate additional chemical matter |
Table 6. Targets Ranked As Under Consideration and in Assay Development and Screening Stages
| target name (abbreviation) | Pf gene ID | key questions |
|---|---|---|
| cytosolic seryl-tRNA synthetase (SerRS) | PF3D7_0717700.1 | chemical starting points; TCP fit |
| V-Type H+ ATPase | includes PF3D7_0406100, PF3D7_0806800, PF3D7_1311900 | generate chemical matter; understand resistance profile, druggability, and TCP fit |
| heat shock protein 90 (HSP90) | PF3D7_0708400 | selectivity; more chemical starting points |
| adenylyl cyclase beta (AC beta) | PF3D7_0802600 | TCP fit; more potent inhibitors; selectivity |
| histone acetyltransferase GCN5 (GCN5) | PF3D7_0823300 | rate of kill; chemical starting points |
| phosphodiesterase beta (PDEβ) | PF3D7_1321500 | resistance potential TCP fit; More chemical starting points; chemical tools for validation |
| aminopeptidase P (APP) | PF3D7_1454400 | TCP fit; selectivity; chemical tools |
| cysteine tRNA synthetase (CysRS) | PF3D7_1015200.1 | protein expressed; development of assay; selectivity |
| hexose transporter (HT) | PF3D7_0204700 | is selectivity versus human orthologues possible? TCP fit; activity against various life cycle stages |
By way of example, we will discuss three key targets. These are intended as general examples to illustrate our approach and thinking, across a range of different targets, and represent a significant focus of work from MalDA members. More information is available in the Supporting Information and on the Web site.
Acetyl CoA Synthetase (PfAcAS) (High Priority Target)
PfAcAS is responsible for the biosynthesis of acetyl coenzyme A from coenzyme A and acetate. We have recently reported the validation of this enzyme. (45,46)
Chemical Validation
Pantothenamides such as MMV689258 and MMV693183 are converted into antimetabolites that interfere with CoA acetylation. (45) In addition, two compounds, MMV019721 and MMV084978 (Figure 3), were found to be active in screens against both P. falciparum asexual blood stages (EC50 values of 460 nM and 370 nM, respectively) and P. berghei liver stages (EC50 values of 2100 nM and 520 nM, respectively). Generation of in vitro resistance to these compounds, followed by whole-genome sequencing, revealed multiple mutations in the gene encoding PfAcAS. These mutations clustered around the predicted active site of the enzyme. PfAcAS biochemical assays indicated that all test compounds inhibit this enzyme. Pantothenamides and MMV019721 are competitive with respect to coenzyme A, and MMV084978 displays a mix-inhibition mode with respect to acetate.
Figure 3
Figure 3. Structures of tool compounds (see text for references to each structure)
Genetic Validation
Several approaches have indicated the genetic essentiality of this enzyme. The enzyme was reported to be essential in P. berghei (34) and was predicted to have a high likelihood to be essential in a P. falciparum piggyBac insertion mutagenesis screen. (33) Conditional knockdown of the enzyme led to both reduced parasite viability and increased sensitivity to pantothenamides, MMV019721, and MMV084978. In contrast, using CRISPR/Cas9 gene editing to replace the wild-type gene for PfAcAS with allelic variants encoding resistance mutations led to parasites with reduced sensitivity to pantothenamides, MMV019721, and MMV084978.
Resistance Potential
It is possible to generate parasite cell lines in vitro that are resistant to MMV689258, MMV019721, and MMV084978, and studies to define the MIR values are ongoing. (35) One of the pantothenamides shows an MIR of 109. As MMV019721 and MMV084978 appear to bind to different sites on the enzyme, each may have a different resistance susceptibility.
Druggability
Pantothenamides, MMV019721, and MMV084978 are small molecules that fit within typical drug-like space. The pantothenamide MMV693183 meets all criteria for a preclinical candidate and is progressing toward a first-in-human study.
TCP fit
MMV019721 and MMV084978 are active against both asexual blood and liver stage parasites with relatively similar EC50 values. Pantothenamides target both asexual and sexual blood stages but have lower activity against liver stages.
Toxicity
Pantothenamides were very well tolerated in in vivo pharmacokinetic, efficacy, and exploratory toxicology studies. MMV019721 and MMV084978 are at an earlier stage in the discovery pipeline and have not been subject to a detailed assessment of toxicity. However, there is a high degree of selectivity at both the enzyme level (compared to human acetyl CoA synthetase) and cellular levels (compared to HepG2 cells).
Novelty
This is a novel target for malaria. There are reports of inhibitors of fungal AcAS enzymes. (47)
Assay Readiness
Both PfAcAS and HsAcAs have been recombinantly expressed and assays developed for high-throughput screening.
Structural Information
There is no structural information for PfAcAS, which to date is proving challenging to crystallize, in our hands.
As a result of all of these studies, there is strong evidence that PfAcAS is a good drug target and is druggable. The pantothenamide MMV693183 is currently in preclinical development. The identification of alternate series capable of inhibiting PfAcAS would be greatly facilitated by structural information and information regarding inhibitor binding. More work is also required to assess the resistance risk across inhibitor classes. This target has now progressed into drug discovery through MalDA-supported efforts.
Bifunctional Farnesyl/Geranylgeranyl Pyrophosphate Synthase (F/GGPPS; High Priority Target)
Bifunctional farnesyl/geranylgeranyl pyrophosphate synthase is a key enzyme in isoprenoid biosynthesis that synthesizes C15 and C20 prenyl chains. Prenyl chains are the substrates of a number of prenyltranferases resulting in isoprenoid products essential for parasite survival.
Chemical Validation. (48)
MMV019313 (Figure 3) inhibits F/GGPPS activity in enzymatic assays. Generation of in vitro resistance to this compound, followed by whole-genome sequencing, revealed mutations in F/GGPPS (S228T). Overexpression of F/GGPPS in parasites was sufficient to confer resistance to MMV019313. Overexpression of the F/GGPPS(S228T)-GFP variant, even at moderate levels, resulted in an 18-fold increase in the EC50 value of MMV019313.
Genetic Validation
The essentiality of this enzyme has been demonstrated via several different approaches. The P. berghei genome-wide screen showed it to be essential. (34) The P. falciparum PiggyBac insertion mutagenesis screen shows that the enzyme is nonmutable in its coding sequence. (33) Conditional knockdown studies confirm essentiality in vitro. S288T allelic replacement parasite lines recapitulate the resistance phenotype of drug-selected lines. Further studies are required to ascertain whether these changes represent indirect resistance mechanisms as opposed to being mutations in drug targets
Resistance Potential
Parasites resistant to MMV019313 acquired a S228T mutation in this gene. A 10-fold shift in susceptibility was observed compared to the wild type. The MIR was determined to be 108.
Druggability
There is current confidence that drug-like compounds can be identified. MMV019313 is a small molecule within the drug-like space even if it needs optimization to become a drug, suggesting that small molecule inhibitors can be identified.
TCP fit
MMV019313 shows asexual blood stage activity (EC50 270 nM) and complies with TCP-1. The compound has not yet been tested for gametocyte activity. It is not active against liver stages.
Toxicity
Human orthologues exist, and assays are available. MMV019313 inhibits the enzymatic activity of PfF/GGPPS but not human FPPS or GGPPS.
Novelty
PfF/GGPPS is a validated target for malaria. Current drugs for this target in other disease areas show poor bioavailability and selectivity. The new tool compound is a small molecule that is selective and has a distinct mode of inhibition compared to current drugs.
Assay Readiness
Structural Information
A crystal structure is available for PvF/GGPPS, which allows for the generation of structural models for other Plasmodium homologues.
The discovery of a new small molecule binding to a novel site, with superior druggability to that of the previously established inhibitor binding site, makes this target very attractive.
Monoacylglycerol Lipase PfMAGL (New and Emerging)
Human monoacylglycerol lipase (MAGL) catalyzes the hydrolysis of a variety of monoglycerides into fatty acids and glycerol. In P. falciparum, this enzyme has been reported to play a role in processing these monoglycerides, including palmitoyl and oleoyl glycerols. (50)
Chemical Validation
The natural product, salinipostin A, (51) and the lipid metabolism inhibitor, orlistat (Figure 3), (50) were shown to be potent against P. falciparum asexual blood stage W2 parasites with EC50 values of 50 nM and 280 nM, respectively. Potent inhibition of recombinant PfMAGL using hits from a small library of triazole–urea inhibitors strongly correlated with in vitro antiplasmodial activity against W2 parasites.
Genetic Validation
Genetic essentiality has been shown in the P. falciparum piggyBac screen. (33)
Resistance Potential
In vitro resistance selection experiments with salinipostin A using a high parasite inoculum (109) in a genetically engineered Dd2 parasite line with an increased mutation rate (Dd2_Polδ) yielded parasites that showed 2- to 9-fold reductions in sensitivity. However, no mutations were observed in PfMAGL in this experiment. Instead, all resistant parasites cloned had SNPs in the “protein of relevant evolutionary and lymphoid interest” (PRELI) domain-containing protein of unknown function (PF3D7_1324400) with five of six clones harboring A20V, P102L, and T145I mutations in the coding sequence, while the sixth clone had a point mutation in intron 1 that has an unknown impact on expression levels. Mutations at S725Y and E507K in the V-type H+-translocating pyrophosphatase (PF3D7_1235200) were also observed in three out of six clones.
Druggability
Salinipostin A is a natural product, while orlistat is prescribed for obesity. The potent activity of these compounds against P. falciparum proliferation and recombinant PfMAGL highlights the feasibility of exploring their respective scaffolds for structure–activity relationship studies to design specific small molecule inhibitors of PfMAGL. However, new series that are more attractive from a medicinal chemistry perspective would increase the druggability confidence.
TCP Fit
Salinipostin A and orlistat are active against asexual blood stages at nanomolar EC50 values. However, the activity of these compounds against liver stage parasites and gametocytes has yet to be investigated.
Toxicity
Salinipostin A has a selectivity index >1000 for P. falciparum asexual blood stage parasites compared to a variety of mammalian cell lines including human foreskin fibroblasts (HFF), HEK293T (human kidney), U2OS (human osteosarcoma), and AsPC-1 (human pancreatic adenocarcinoma). (51)
Novelty
This is a novel target for malaria.
Assay Readiness
There already exist platforms to study this enzyme, including a fluorogenic substrate assay to assess the characteristics of the recombinant PfMAGL with various fluorogenic lipid ester substrates bearing different chain lengths. Parasite lines overexpressing PfMAGL from an exogenously transfected plasmid have been developed. In addition, there is a competition assay for active site labeling of PfMAGL and human MAGL with the broad-spectrum serine hydrolase ABP fluorophosphonate-rhodamine (FP-Rho) to screen compounds for their ability to compete for the active sites of the two enzymes and identify highly potent and selective hits.
Structural Information
The crystal structure of the human MAGL is available (PDB: 3jw8) and a predicted PfMAGL homology model templated on this structure has been published. (50)
This target shows promise as an antimalarial target, based on the good correlation between enzyme and parasite inhibition and the low propensity of resistance for these inhibitors. The availability of assays will facilitate screens to identify new potent and selective hits. Further experiments are required to complete the chemical and genetic validation and to assess the TCP fit for this target.
Future Perspectives
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Phenotypic Screening
In the past 20 years, drug discovery against malaria has largely focused on phenotypic screening approaches, due to the relative lack of robustly validated targets. Many of the readily available compounds in lead-like and drug-like space have already been screened against P. falciparum, leading to a lack of novel compound libraries to screen, particularly those addressing novel areas of chemical space. Therefore, an increased effort focusing on target-based approaches is merited. In the past 10 years, significant progress has been made in identifying and validating potential drug targets for malaria. Information about antimalarial drug targets is being captured in a Web site by the International Union of Basic and Clinical Pharmacology (https://www.guidetomalariapharmacology.org/malaria/).
It is important that the most appropriate drug targets are carefully selected for progression into drug discovery. Despite the success in identifying clinical candidates for malaria, we must be mindful of the high attrition rate in clinical development, as is seen for all drug development programs. For infectious diseases, the typical success rate from entry to phase 1 clinical studies to compound registration is 19–25%. (52,53) Success in drug discovery and subsequent clinical development is highly dependent upon both the selection of the molecular target and the properties of the compounds progressed.
The properties of a particular molecule will be at least in part dependent on the druggability of the target. Key challenges in molecular designs for antimalarial drug discovery include compounds with a long half-life, suitable for single-dose oral treatment and chemoprotection; oral bioavailability; stability for storage at room temperature in tropical conditions for extended periods; a low cost of goods; and good safety profiles.
Resistance is a key issue, particularly for asexual blood stage infections. It is not totally clear whether resistance is solely a function of the target or the compound or both. Some targets are known to be particularly susceptible to mutations (for example, dihydroorotate dehydrogenase). For targets with several different drug binding pockets (e.g., tRNA synthetases; due to multiple substrates), each may have a different risk of mutation.
As well as identifying the most promising molecular targets, we also need to identify for each target the most appropriate hit and drug discovery strategies to derive therapies with desired profiles. For example, fragment-based drug discovery approaches can be useful to optimize the physicochemical properties of molecules as they are developed.
How Do We Identify Additional Drug Targets in Malaria?
First, there are still many phenotypically identified compounds for which the mode of action remains to be determined. Some of these may be acting on more than one target or acting on nonprotein targets. Compounds that demonstrate polypharmacology may be desirable to reduce the resistance risk; however, the design of such molecules is in its early stages.
Second, we are investigating a “big-data” approach to identify potential new targets. As an initial triage, we have analyzed the P. falciparum genome and cross-referenced this against a number of different databases (Figure 4A), to identify targets that it might be valuable to investigate. The workflow is as follows:
Figure 4
Figure 4. (A) Analysis of the P. falciparum genome categorizing targets according to their predicted essentiality, druggability, and the presence of mammalian orthologs. The number of proteins in each category is shown in parentheses. (B) Analysis of high value targets, according to tool compounds, the presence of mammalian orthologs, and proof of concept in humans. The number of proteins in each category is shown in parentheses. Where there is only one protein in a category, it is stated explicitly. Most MalDA targets fall into the light blue or violet regions.
•Essentiality. To determine if the target is essential in Plasmodium, we have used the data obtained through saturation mutagenesis (33) or functional analysis. (34)
•Druggability. We used the recently published method of Wang and coauthors to assess ligand binding ability. (54,55) We extracted the 236 InterPro domains listed as ligandable and searched PlasmoDB for proteins with these domains.
•Enzymes. We also included proteins annotated with an EC number or predicted to catalyze a reaction because many are known to be good drug targets. Many enzymes were also considered ligandable using the method above (e.g., kinases).
•Mammalian Orthologue. We examined whether a human orthologue exists using the ortholog search function within PlasmoDB. (56) The lack of a mammalian orthologue has traditionally been considered an attractive feature for anti-infective drug targets. However, it is important that the presence of a human orthologue is not used as a reason for deprioritizing a target: (1) Where there is a human orthologue, it is very often possible to obtain high levels of selectivity (for example, against P. falciparum dihydrofolate reductase). (2) Sometimes there are very different levels of “vulnerability” between a pathogen enzyme and its orthologues. (3) Plasmodium targets for which there is not a human orthologue are not always attractive targets. For example, many early, postgenomic drug discovery programs were focused on members of the nonmevalonate pathway of isoprenoid biosynthesis, (57) or other proteins targeted to the apicoplast (including bacterial-type proteins involved in protein biosynthesis), a parasite-specific organelle involved in the production of isoprenoids. (58) While it may be possible to find highly selective inhibitors for such targets, the rate of kill may be slower, as was the case for fosmidomycin (that targets DOXP reductoisomerase), tetracycline, or azithromycin. (59) Another caveat is that some of these druggable parasite-specific targets, such as enoyl-ACP reductase (FabI, PF3D7_0615100), may only be important for the liver or sporozoite stage. (60,61)
This analysis suggests that there are about 300–700 potential drug targets in Plasmodium. These will have different profiles, and inhibitors of these may fulfill different TCPs.
We then did an analysis of the malaria protein targets that have extensive validation, including those with proof-of-concept data in humans (Figure 4B). These include the targets that MalDA has assessed as being high value (Figure 2), along with targets known from current drugs and targets from compounds currently in clinical development, including PI4K, eEF2, and DHODH. (43)
In addition to the annotated Plasmodium genes, there are many genes that have not been annotated, the so-called hypothetical proteins. There may well be attractive targets, which could be very different structurally and functionally from human proteins, potentially allowing for selective inhibitors. It is also important to consider that the definition of druggability, for this exercise, is dependent on the existence of ligand-bound protein structures in the Protein Data Bank (https://www.rcsb.org/). Proteins that are more difficult to structurally characterize, such as membrane proteins, may have been overlooked. Paradoxically, the more different a Plasmodium protein is from its mammalian ortholog, the more likely it is to not be recognized as druggable. Another important consideration is that there may be nonprotein targets, including rRNAs. Compounds that target the bacterial-type protein biosynthesis machinery, including azithromycin, clindamycin, and tetracycline, have antimalarial activity, although many have a slow rate of kill.
While the focus of this exercise has been to prioritize potential targets for drug discovery, this process will have considerable value in further dissecting the fundamental biology of these parasites. Understanding the biological context of a target is key to understanding how a potential drug target may be exploited in the clinic. Further, since all antimalarials are now given as combination therapies, understanding the background biology is important in selecting combinations. Even for targets that are not deemed suitable from a drug discovery context, this exercise can still provide valuable biological insights into these important pathogens.
One aim of this publication is to stimulate discovery and validation of potential new drug targets for Plasmodium. We hope that it will facilitate efforts in the broader malaria community writ large to continue to contribute valuable insights to support the antimalarial drug development effort. We welcome comments from the community on these and other targets. To that end, we invite comments on our Web site (www.malariaDA.org), which will then be used to annotate a list of potential targets, to be displayed on the Web site.
Supporting Information
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.1c00322.
Assessments of other molecular targets (PDF)
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Author Information
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- Beatriz Baragaña - Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, DD1 5EH, United Kingdom;
https://orcid.org/0000-0002-0959-1113;
- Elizabeth A. Winzeler - Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, United States;https://orcid.org/0000-0002-4049-2113;
- Ian H. Gilbert - Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, DD1 5EH, United Kingdom;https://orcid.org/0000-0002-5238-1314;
- Sabine Ottilie - Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, United States;https://orcid.org/0000-0001-9797-2612
- Francisco Javier Gamo - Global Health, GSK, 28760-Tres Cantos, Madrid, Spain;https://orcid.org/0000-0002-1854-2882
- Daniel E. Goldberg - Division of Infectious Diseases, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States;https://orcid.org/0000-0003-3529-8399
- Amanda K. Lukens - Infectious Disease and Microbiome Program, Broad Institute, Cambridge, Massachusetts 02142, United States; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, United States;https://orcid.org/0000-0002-9560-7643
- Case W. McNamara - Calibr, a Division of The Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, California 92037, United States;https://orcid.org/0000-0002-5754-3407
- Jacquin C. Niles - Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge Massachusetts 02139-4307, United States;https://orcid.org/0000-0002-6250-8796
- Susan Wyllie - Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, DD1 5EH, United Kingdom;https://orcid.org/0000-0001-8810-5605
Contributed equally to this work
Acknowledgments
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This work was supported in part by the Bill & Melinda Gates Foundation (OPP1054480, OPP1193840, OPP1202973 and OPP1032548). Medicines for Malaria Venture is also acknowledged for financial support. Authors from Dundee are part of the Wellcome Centre for Anti-Infectives Research and acknowledge funding from Wellcome (203134/Z/16/Z). The authors would like to acknowledge Dr. Gang Liu of the Bill & Melinda Gates Foundation for his contribution to MalDA.
Note Added After ASAP Publication
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This paper was originally published ASAP on September 15, 2021. Additional corrections were received, and the revised version reposted on September 16, 2021.
References
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This article references 61 other publications.
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- 3Heinemann, M.; Phillips, R. O.; Vinnemeier, C. D.; Rolling, C. C.; Tannich, E.; Rolling, T. High prevalence of asymptomatic malaria infections in adults, Ashanti Region, Ghana, 2018. Malar. J. 2020, 19, 366, DOI: 10.1186/s12936-020-03441-z[Crossref], [PubMed], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3s7gsVeltQ%253D%253D&md5=7056c75560062d7fa69aa04c2b320e61High prevalence of asymptomatic malaria infections in adults, Ashanti Region, Ghana, 2018Heinemann Melina; Rolling Thierry; Heinemann Melina; Vinnemeier Christof D; Heinemann Melina; Phillips Richard O; Vinnemeier Christof D; Rolling Christina C; Rolling Christina C; Tannich Egbert; Tannich Egbert; Rolling Thierry; Rolling Thierry; Rolling ThierryMalaria journal (2020), 19 (1), 366 ISSN:.BACKGROUND: Ghana is among the high-burden countries for malaria infections and recently reported a notable increase in malaria cases. While asymptomatic parasitaemia is increasingly recognized as a hurdle for malaria elimination, studies on asymptomatic malaria are scarce, and usually focus on children and on non-falciparum species. The present study aims to assess the prevalence of asymptomatic Plasmodium falciparum and non-falciparum infections in Ghanaian adults in the Ashanti region during the high transmission season. METHODS: Asymptomatic adult residents from five villages in the Ashanti Region, Ghana, were screened for Plasmodium species by rapid diagnostic test (RDT) and polymerase chain reaction (PCR) during the rainy season. Samples tested positive were subtyped using species-specific real-time PCR. For all Plasmodium ovale infections additional sub-species identification was performed. RESULTS: Molecular prevalence of asymptomatic Plasmodium infection was 284/391 (73%); only 126 (32%) infections were detected by RDT. While 266 (68%) participants were infected with Plasmodium falciparum, 33 (8%) were infected with Plasmodium malariae and 34 (9%) with P. ovale. The sub-species P. ovale curtisi and P. ovale wallikeri were identified to similar proportions. Non-falciparum infections usually presented as mixed infections with P. falciparum. CONCLUSIONS: Most adult residents in the Ghanaian forest zone are asymptomatic Plasmodium carriers. The high Plasmodium prevalence not detected by RDT in adults highlights that malaria eradication efforts must target all members of the population. Beneath Plasmodium falciparum, screening and treatment must also include infections with P. malariae, P. o. curtisi and P. o. wallikeri.
- 4Burrows, J. N.; Duparc, S.; Gutteridge, W. E.; Hooft van Huijsduijnen, R.; Kaszubska, W.; Macintyre, F.; Mazzuri, S.; Möhrle, J. J.; Wells, T. N. C. New developments in anti-malarial target candidate and product profiles. Malar. J. 2017, 16, 26, DOI: 10.1186/s12936-016-1675-x[Crossref], [PubMed], [CAS], Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjsFCqu7g%253D&md5=17984994f7a29c9fb184faa5214d4d35New developments in anti-malarial target candidate and product profilesBurrows, Jeremy N.; Duparc, Stephan; Gutteridge, Winston E.; Hooft van Huijsduijnen, Rob; Kaszubska, Wiweka; MacIntyre, Fiona; Mazzuri, Sebastien; Mohrle, Jorg J.; Wells, Timothy N. C.Malaria Journal (2017), 16 (), 26/1-26/29CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)A review. A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti-malarial drugs are discovered and developed have led to a dramatic increase in the no. and diversity of new mols. presently in pre-clin. and early clin. development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Subregion, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting mols., or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well-tolerated to be used in vulnerable populations: in pregnancy, esp. the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria.
- 5Burrows, J. N; Hooft van Huijsduijnen, R.; Mohrle, J. J; Oeuvray, C.; Wells, T. N. Designing the next generation of medicines for malaria control and eradication. Malar. J. 2013, 12, 187, DOI: 10.1186/1475-2875-12-187[Crossref], [PubMed], [CAS], Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sjgsVSisA%253D%253D&md5=c4283af83b04bc217f40528dde196e23Designing the next generation of medicines for malaria control and eradicationBurrows Jeremy N; van Huijsduijnen Rob Hooft; Mohrle Jorg J; Oeuvray Claude; Wells Timothy N CMalaria journal (2013), 12 (), 187 ISSN:.In the fight against malaria new medicines are an essential weapon. For the parts of the world where the current gold standard artemisinin combination therapies are active, significant improvements can still be made: for example combination medicines which allow for single dose regimens, cheaper, safer and more effective medicines, or improved stability under field conditions. For those parts of the world where the existing combinations show less than optimal activity, the priority is to have activity against emerging resistant strains, and other criteria take a secondary role. For new medicines to be optimal in malaria control they must also be able to reduce transmission and prevent relapse of dormant forms: additional constraints on a combination medicine. In the absence of a highly effective vaccine, new medicines are also needed to protect patient populations. In this paper, an outline definition of the ideal and minimally acceptable characteristics of the types of clinical candidate molecule which are needed (target candidate profiles) is suggested. In addition, the optimal and minimally acceptable characteristics of combination medicines are outlined (target product profiles). MMV presents now a suggested framework for combining the new candidates to produce the new medicines. Sustained investment over the next decade in discovery and development of new molecules is essential to enable the long-term delivery of the medicines needed to combat malaria.
- 6Dembélé, L.; Franetich, J.-F.; Lorthiois, A.; Gego, A.; Zeeman, A.-M.; Kocken, C. H. M.; Le Grand, R.; Dereuddre-Bosquet, N.; van Gemert, G.-J.; Sauerwein, R.; Vaillant, J.-C.; Hannoun, L.; Fuchter, M. J.; Diagana, T. T.; Malmquist, N. A.; Scherf, A.; Snounou, G.; Mazier, D. Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures. Nat. Med. 2014, 20, 307– 312, DOI: 10.1038/nm.3461[Crossref], [PubMed], [CAS], Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFaqt7w%253D&md5=80fad73cf8a19f15df33e949540f02f7Persistence and activation of malaria hypnozoites in long-term primary hepatocyte culturesDembele, Laurent; Franetich, Jean-Francois; Lorthiois, Audrey; Gego, Audrey; Zeeman, Anne-Marie; Kocken, Clemens H. M.; Le Grand, Roger; Dereuddre-Bosquet, Nathalie; van Gemert, Geert-Jan; Sauerwein, Robert; Vaillant, Jean-Christophe; Hannoun, Laurent; Fuchter, Matthew J.; Diagana, Thierry T.; Malmquist, Nicholas A.; Scherf, Artur; Snounou, Georges; Mazier, DominiqueNature Medicine (New York, NY, United States) (2014), 20 (3), 307-312CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)Malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of Plasmodium vivax and Plasmodium ovale, hinder global efforts to control and eliminate malaria. As primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. Currently, analyses of hypnozoites, including screening of compds. that would eliminate them, can only be made using common macaque models, principally Macaca rhesus and Macaca fascicularis, exptl. infected with the relapsing Plasmodium cynomolgi. Here, we present a protocol for long-term in vitro cultivation of P. cynomolgi-infected M. fascicularis primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept expt., we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation. The protocol presented may further enable investigations of hypnozoite biol. and the search for compds. that kill hypnozoites or disrupt their quiescence.
- 7Barrett, M. P.; Kyle, D. E.; Sibley, L. D.; Radke, J. B.; Tarleton, R. L. Protozoan persister-like cells and drug treatment failure. Nat. Rev. Microbiol. 2019, 17, 607– 620, DOI: 10.1038/s41579-019-0238-x[Crossref], [PubMed], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1eksLfO&md5=0a1415d70f7d0c420666c5999854f51cProtozoan persister-like cells and drug treatment failureBarrett, Michael P.; Kyle, Dennis E.; Sibley, L. David; Radke, Joshua B.; Tarleton, Rick L.Nature Reviews Microbiology (2019), 17 (10), 607-620CODEN: NRMACK; ISSN:1740-1526. (Nature Research)Antimicrobial treatment failure threatens our ability to control infections. In addn. to antimicrobial resistance, treatment failures are increasingly understood to derive from cells that survive drug treatment without selection of genetically heritable mutations. Parasitic protozoa, such as Plasmodium species that cause malaria, Toxoplasma gondii and kinetoplastid protozoa, including Trypanosoma cruzi and Leishmania spp., cause millions of deaths globally. These organisms can evolve drug resistance and they also exhibit phenotypic diversity, including the formation of quiescent or dormant forms that contribute to the establishment of long-term infections that are refractory to drug treatment, which we refer to as 'persister-like cells'. In this Review, we discuss protozoan persister-like cells that have been linked to persistent infections and discuss their impact on therapeutic outcomes following drug treatment.
- 8Abraham, M.; Gagaring, K.; Martino, M. L.; Vanaerschot, M.; Plouffe, D. M.; Calla, J.; Godinez-Macias, K. P.; Du, A. Y.; Wree, M.; Antonova-Koch, Y.; Eribez, K.; Luth, M. R.; Ottilie, S.; Fidock, D. A.; McNamara, C. W.; Winzeler, E. A. Probing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation Antimalarials. ACS Infect. Dis. 2020, 6, 613– 628, DOI: 10.1021/acsinfecdis.9b00482[ACS Full Text
], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjsVOmsLY%253D&md5=6ee44448c30e2dff0d6707d8a7ad3d1aProbing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation AntimalarialsAbraham, Matthew; Gagaring, Kerstin; Martino, Marisa L.; Vanaerschot, Manu; Plouffe, David M.; Calla, Jaeson; Godinez-Macias, Karla P.; Du, Alan Y.; Wree, Melanie; Antonova-Koch, Yevgeniya; Eribez, Korina; Luth, Madeline R.; Ottilie, Sabine; Fidock, David A.; McNamara, Case W.; Winzeler, Elizabeth A.ACS Infectious Diseases (2020), 6 (4), 613-628CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)Most phenotypic screens aiming to discover new antimalarial chemotypes begin with low cost, high-throughput tests against the asexual blood stage (ABS) of the malaria parasite life cycle. Compds. active against the ABS are then sequentially tested in more difficult assays that predict whether a compd. has other beneficial attributes. Although applying this strategy to new chem. libraries may yield new leads, repeated iterations may lead to diminishing returns and the rediscovery of chemotypes hitting well-known targets. Here, we adopted a different strategy to find starting points, testing ∼70,000 open source small mols. from the Global Health Chem. Diversity Library for activity against the liver stage, mature sexual stage, and asexual blood stage malaria parasites in parallel. In addn., instead of using an asexual assay that measures accumulated parasite DNA in the presence of compd. (SYBR green), a real time luciferase-dependent parasite viability assay was used that distinguishes slow-acting (delayed death) from fast-acting compds. Among 382 scaffolds with the activity confirmed by dose response (<10 μM), we discovered 68 novel delayed-death, 84 liver stage, and 68 stage V gametocyte inhibitors as well. Although 89% of the evaluated compds. had activity in only a single life cycle stage, we discovered six potent (half-maximal inhibitory concn. of <1 μM) multistage scaffolds, including a novel cytochrome bc1 chemotype. Our data further show the luciferase-based assays have higher sensitivity. Chemoinformatic anal. of pos. and neg. compds. identified scaffold families with a strong enrichment for activity against specific or multiple stages. - 9Antonova-Koch, Y.; Meister, S.; Abraham, M.; Luth, M. R.; Ottilie, S.; Lukens, A. K.; Sakata-Kato, T.; Vanaerschot, M.; Owen, E.; Jado, J. C.; Maher, S. P.; Calla, J.; Plouffe, D.; Zhong, Y.; Chen, K.; Chaumeau, V.; Conway, A. J.; McNamara, C. W.; Ibanez, M.; Gagaring, K.; Serrano, F. N.; Eribez, K.; Taggard, C. M.; Cheung, A. L.; Lincoln, C.; Ambachew, B.; Rouillier, M.; Siegel, D.; Nosten, F.; Kyle, D. E.; Gamo, F.-J.; Zhou, Y.; Llinás, M.; Fidock, D. A.; Wirth, D. F.; Burrows, J.; Campo, B.; Winzeler, E. A. Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. Science 2018, 362, eaat9446, DOI: 10.1126/science.aat9446
- 10Gamo, F. J.; Sanz, L. M.; Vidal, J.; de Cozar, C.; Alvarez, E.; Lavandera, J. L.; Vanderwall, D. E.; Green, D. V.; Kumar, V.; Hasan, S.; Brown, J. R.; Peishoff, C. E.; Cardon, L. R.; Garcia-Bustos, J. F. Thousands of chemical starting points for antimalarial lead identification. Nature 2010, 465, 305– 310, DOI: 10.1038/nature09107[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmt1Ois7k%253D&md5=a1fd8c0b89a5650ecba31f5456928b42Thousands of chemical starting points for antimalarial lead identificationGamo, Francisco-Javier; Sanz, Laura M.; Vidal, Jaume; de Cozar, Cristina; Alvarez, Emilio; Lavandera, Jose-Luis; Vanderwall, Dana E.; Green, Darren V. S.; Kumar, Vinod; Hasan, Samiul; Brown, James R.; Peishoff, Catherine E.; Cardon, Lon R.; Garcia-Bustos, Jose F.Nature (London, United Kingdom) (2010), 465 (7296), 305-310CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chem. class of antimalarials has been introduced into clin. practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compds. in GlaxoSmithKline's chem. library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 μM concn. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compds. originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chem. structures and assocd. data are hereby made public to encourage addnl. drug lead identification efforts and further research into this disease.
- 11Plouffe, D. M.; Wree, M.; Du, A. Y.; Meister, S.; Li, F.; Patra, K.; Lubar, A.; Okitsu, S. L.; Flannery, E. L.; Kato, N.; Tanaseichuk, O.; Comer, E.; Zhou, B.; Kuhen, K.; Zhou, Y.; Leroy, D.; Schreiber, S. L.; Scherer, C. A.; Vinetz, J.; Winzeler, E. A. High-Throughput Assay and Discovery of Small Molecules that Interrupt Malaria Transmission. Cell Host Microbe 2016, 19, 114– 126, DOI: 10.1016/j.chom.2015.12.001[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlKrsQ%253D%253D&md5=297ed2ccee9f8fc5fc2024f2fecffae0High-Throughput Assay and Discovery of Small Molecules that Interrupt Malaria TransmissionPlouffe, David M.; Wree, Melanie; Du, Alan Y.; Meister, Stephan; Li, Fengwu; Patra, Kailash; Lubar, Aristea; Okitsu, Shinji L.; Flannery, Erika L.; Kato, Nobutaka; Tanaseichuk, Olga; Comer, Eamon; Zhou, Bin; Kuhen, Kelli; Zhou, Yingyao; Leroy, Didier; Schreiber, Stuart L.; Scherer, Christina A.; Vinetz, Joseph; Winzeler, Elizabeth A.Cell Host & Microbe (2016), 19 (1), 114-126CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)Preventing transmission is an important element of malaria control. However, most of the current available methods to assay for malaria transmission blocking are relatively low throughput and cannot be applied to large chem. libraries. We have developed a high-throughput and cost-effective assay, the Saponin-lysis Sexual Stage Assay (SaLSSA), for identifying small mols. with transmission-blocking capacity. SaLSSA anal. of 13,983 unique compds. uncovered that >90% of well-characterized antimalarials, including endoperoxides and 4-aminoquinolines, as well as compds. active against asexual blood stages, lost most of their killing activity when parasites developed into metabolically quiescent stage V gametocytes. On the other hand, we identified compds. with consistent low nanomolar transmission-blocking activity, some of which showed cross-reactivity against asexual blood and liver stages. The data clearly emphasize substantial physiol. differences between sexual and asexual parasites and provide a tool and starting points for the discovery and development of transmission-blocking drugs.
- 12Van Voorhis, W. C.; Adams, J. H.; Adelfio, R.; Ahyong, V.; Akabas, M. H.; Alano, P.; Alday, A.; Alemán Resto, Y.; Alsibaee, A.; Alzualde, A.; Andrews, K. T.; Avery, S. V.; Avery, V. M.; Ayong, L.; Baker, M.; Baker, S.; Ben Mamoun, C.; Bhatia, S.; Bickle, Q.; Bounaadja, L.; Bowling, T.; Bosch, J.; Boucher, L. E.; Boyom, F. F.; Brea, J.; Brennan, M.; Burton, A.; Caffrey, C. R.; Camarda, G.; Carrasquilla, M.; Carter, D.; Belen Cassera, M.; Chih-Chien Cheng, K.; Chindaudomsate, W.; Chubb, A.; Colon, B. L.; Colón-López, D. D.; Corbett, Y.; Crowther, G. J.; Cowan, N.; D’Alessandro, S.; Le Dang, N.; Delves, M.; DeRisi, J. L.; Du, A. Y.; Duffy, S.; Abd El-Salam El-Sayed, S.; Ferdig, M. T.; Fernández Robledo, J. A.; Fidock, D. A.; Florent, I.; Fokou, P. V. T.; Galstian, A.; Gamo, F. J.; Gokool, S.; Gold, B.; Golub, T.; Goldgof, G. M.; Guha, R.; Guiguemde, W. A.; Gural, N.; Guy, R. K.; Hansen, M. A. E.; Hanson, K. K.; Hemphill, A.; Hooft van Huijsduijnen, R.; Horii, T.; Horrocks, P.; Hughes, T. B.; Huston, C.; Igarashi, I.; Ingram-Sieber, K.; Itoe, M. A.; Jadhav, A.; Naranuntarat Jensen, A.; Jensen, L. T.; Jiang, R. H. Y.; Kaiser, A.; Keiser, J.; Ketas, T.; Kicka, S.; Kim, S.; Kirk, K.; Kumar, V. P.; Kyle, D. E.; Lafuente, M. J.; Landfear, S.; Lee, N.; Lee, S.; Lehane, A. M.; Li, F.; Little, D.; Liu, L.; Llinás, M.; Loza, M. I.; Lubar, A.; Lucantoni, L.; Lucet, I.; Maes, L.; Mancama, D.; Mansour, N. R.; March, S.; McGowan, S.; Medina Vera, I.; Meister, S.; Mercer, L.; Mestres, J.; Mfopa, A. N.; Misra, R. N.; Moon, S.; Moore, J. P.; Morais Rodrigues da Costa, F.; Müller, J.; Muriana, A.; Nakazawa Hewitt, S.; Nare, B.; Nathan, C.; Narraidoo, N.; Nawaratna, S.; Ojo, K. K.; Ortiz, D.; Panic, G.; Papadatos, G.; Parapini, S.; Patra, K.; Pham, N.; Prats, S.; Plouffe, D. M.; Poulsen, S.-A.; Pradhan, A.; Quevedo, C.; Quinn, R. J.; Rice, C. A.; Abdo Rizk, M.; Ruecker, A.; St. Onge, R.; Salgado Ferreira, R.; Samra, J.; Robinett, N. G.; Schlecht, U.; Schmitt, M.; Silva Villela, F.; Silvestrini, F.; Sinden, R.; Smith, D. A.; Soldati, T.; Spitzmüller, A.; Stamm, S. M.; Sullivan, D. J.; Sullivan, W.; Suresh, S.; Suzuki, B. M.; Suzuki, Y.; Swamidass, S. J.; Taramelli, D.; Tchokouaha, L. R. Y.; Theron, A.; Thomas, D.; Tonissen, K. F.; Townson, S.; Tripathi, A. K.; Trofimov, V.; Udenze, K. O.; Ullah, I.; Vallieres, C.; Vigil, E.; Vinetz, J. M.; Voong Vinh, P.; Vu, H.; Watanabe, N.-a.; Weatherby, K.; White, P. M.; Wilks, A. F.; Winzeler, E. A.; Wojcik, E.; Wree, M.; Wu, W.; Yokoyama, N.; Zollo, P. H. A.; Abla, N.; Blasco, B.; Burrows, J.; Laleu, B.; Leroy, D.; Spangenberg, T.; Wells, T.; Willis, P. A. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. PLoS Pathog. 2016, 12, e1005763, DOI: 10.1371/journal.ppat.1005763[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVelu7rL&md5=0545e9836cf38a96b4ab000ca0a810bfOpen source drug discovery with the malaria box compound collection for neglected diseases and beyondVan Voorhis, Wesley C.; Adams, John H.; Adelfio, Roberto; Ahyong, Vida; Akabas, Myles H.; Alano, Pietro; Alday, Aintzane; Aleman Resto, Yesmalie; Alsibaee, Aishah; Alzualde, Ainhoa; Andrews, Katherine T.; Avery, Simon V.; Avery, Vicky M.; Ayong, Lawrence; Baker, Mark; Baker, Stephen; Ben Mamoun, Choukri; Bhatia, Sangeeta; Bickle, Quentin; Bounaadja, Lotfi; Bowling, Tana; Bosch, Jurgen; Boucher, Lauren E.; Boyom, Fabrice F.; Brea, Jose; Brennan, Marian; Burton, Audrey; Caffrey, Conor R.; Camarda, Grazia; Carrasquilla, Manuela; Carter, Dee; Cassera, Maria Belen; Cheng, Ken Chih-Chien; Chindaudomsate, Worathad; Chubb, Anthony; Colon, Beatrice L.; Colon-Lopez, Daisy D.; Corbett, Yolanda; Crowther, Gregory J.; Cowan, Noemi; D'Alessandro, Sarah; Dang, Na Le; Delves, Michael; De Risi, Joseph L.; Du, Alan Y.; Duffy, Sandra; El-Sayed, Shimaa Abd El-Salam; Ferdig, Michael T.; Fernandez Robledo, Jose A.; Fidock, David A.; Florent, Isabelle; Fokou, Patrick V. T.; Galstian, Ani; Gamo, Francisco Javier; Gokool, Suzanne; Gold, Ben; Golub, Todd; Goldgof, Gregory M.; Guha, Rajarshi; Guiguemde, W. Armand; Gural, Nil; Guy, R. Kiplin; Hansen, Michael A. E.; Hanson, Kirsten K.; Hemphill, Andrew; Hooft van Huijsduijnen, Rob; Horii, Takaaki; Horrocks, Paul; Hughes, Tyler B.; Huston, Christopher; Igarashi, Ikuo; Ingram-Sieber, Katrin; Itoe, Maurice A.; Jadhav, Ajit; Jensen, Amornrat Naranuntarat; Jensen, Laran T.; Jiang, Rays H. Y.; Kaiser, Annette; Keiser, Jennifer; Ketas, Thomas; Kicka, Sebastien; Kim, Sunyoung; Kirk, Kiaran; Kumar, Vidya P.; Kyle, Dennis E.; Lafuente, Maria Jose; Landfear, Scott; Lee, Nathan; Lee, Sukjun; Lehane, Adele M.; Li, Fengwu; Little, David; Liu, Liqiong; Llinas, Manuel; Loza, Maria I.; Lubar, Aristea; Lucantoni, Leonardo; Lucet, Isabelle; Maes, Louis; Mancama, Dalu; Mansour, Nuha R.; March, Sandra; McGowan, Sheena; Vera, Iset Medina; Meister, Stephan; Mercer, Luke; Mestres, Jordi; Mfopa, Alvine N.; Misra, Raj N.; Moon, Seunghyun; Moore, John P.; Morais Rodrigues da Costa, Francielly; Muller, Joachim; Muriana, Arantza; Hewitt, Stephen Nakazawa; Nare, Bakela; Nathan, Carl; Narraidoo, Nathalie; Nawaratna, Sujeevi; Ojo, Kayode K.; Ortiz, Diana; Panic, Gordana; Papadatos, George; Parapini, Silvia; Patra, Kailash; Pham, Ngoc; Prats, Sarah; Plouffe, David M.; Poulsen, Sally-Ann; Pradhan, Anupam; Quevedo, Celia; Quinn, Ronald J.; Rice, Christopher A.; Rizk, Mohamed Abdo; Ruecker, Andrea; St. Onge, Robert; Ferreira, Rafaela Salgado; Samra, Jasmeet; Robinett, Natalie G.; Schlecht, Ulrich; Schmitt, Marjorie; Villela, Filipe Silva; Silvestrini, Francesco; Sinden, Robert; Smith, Dennis A.; Soldati, Thierry; Spitzmuller, Andreas; Stamm, Serge Maximilian; Sullivan, David J.; Sullivan, William; Suresh, Sundari; Suzuki, Brian M.; Suzuki, Yo; Swamidass, S. Joshua; Taramelli, Donatella; Tchokouaha, Lauve R. Y.; Theron, Anjo; Thomas, David; Tonissen, Kathryn F.; Townson, Simon; Tripathi, Abhai K.; Trofimov, Valentin; Udenze, Kenneth O.; Ullah, Imran; Vallieres, Cindy; Vigil, Edgar; Vinetz, Joseph M.; Vinh, Phat Voong; Vu, Hoan; Watanabe, Nao-aki; Weatherby, Kate; White, Pamela M.; Wilks, Andrew F.; Winzeler, Elizabeth A.; Wojcik, Edward; Wree, Melanie; Wu, Wesley; Yokoyama, Naoaki; Zollo, Paul H. A.; Abla, Nada; Blasco, Benjamin; Burrows, Jeremy; Laleu, Benoit; Leroy, Didier; Spangenberg, Thomas; Wells, Timothy; Willis, Paul A.PLoS Pathogens (2016), 12 (7), e1005763/1-e1005763/23CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biol. is present in universities, whereas the focus of medicinal chem. is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could esp. be bridged through a scale-up of open sharing of phys. compds., which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compds. representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-anal. of the combined dataset. The combined biochem. and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compds. active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addn., many compds. demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicol., pharmacokinetic and metabolic properties were collected on all the compds., assisting in the selection of the most promising candidates for murine proof-of-concept expts. and medicinal chem. programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biol. assays involving human pathogens into drug discovery starting points, by providing open access to new families of mols., and emphasize how a small addnl. investment made to help acquire and distribute compds., and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chem. efforts.
- 13Goodnow, R. A., Jr.; Dumelin, C. E.; Keefe, A. D. DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nat. Rev. Drug Discovery 2017, 16, 131– 147, DOI: 10.1038/nrd.2016.213[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVKkurjM&md5=7ca97b01d75e600378799baf77665c07DNA-encoded chemistry: enabling the deeper sampling of chemical spaceGoodnow, Robert A. Jr; Dumelin, Christoph E.; Keefe, Anthony D.Nature Reviews Drug Discovery (2017), 16 (2), 131-147CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. DNA-encoded chem. library technologies are increasingly being adopted in drug discovery for hit and lead generation. DNA-encoded chem. enables the exploration of chem. spaces four to five orders of magnitude more deeply than is achievable by traditional high-throughput screening methods. Operation of this technol. requires developing a range of capabilities including aq. synthetic chem., building block acquisition, oligonucleotide conjugation, large-scale mol. biol. transformations, selection methodologies, PCR, sequencing, sequence data anal. and the anal. of large chem. spaces. This Review provides an overview of the development and applications of DNA-encoded chem., highlighting the challenges and future directions for the use of this technol.
- 14Yuthavong, Y.; Tarnchompoo, B.; Vilaivan, T.; Chitnumsub, P.; Kamchonwongpaisan, S.; Charman, S. A.; McLennan, D. N.; White, K. L.; Vivas, L.; Bongard, E.; Thongphanchang, C.; Taweechai, S.; Vanichtanankul, J.; Rattanajak, R.; Arwon, U.; Fantauzzi, P.; Yuvaniyama, J.; Charman, W. N.; Matthews, D. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 16823– 16828, DOI: 10.1073/pnas.1204556109[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1WksL7M&md5=7ef675391becc919f718de74fa61550bMalarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised targetYuthavong, Yongyuth; Tarnchompoo, Bongkoch; Vilaivan, Tirayut; Chitnumsub, Penchit; Kamchonwongpaisan, Sumalee; Charman, Susan A.; McLennan, Danielle N.; White, Karen L.; Vivas, Livia; Bongard, Emily; Thongphanchang, Chawanee; Taweechai, Supannee; Vanichtanankul, Jarunee; Rattanajak, Roonglawan; Arwon, Uthai; Fantauzzi, Pascal; Yuvaniyama, Jirundon; Charman, William N.; Matthews, DavidProceedings of the National Academy of Sciences of the United States of America (2012), 109 (42), 16823-16828, S16823/1-S16823/9CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clin. efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclin. development of a selective, highly efficacious, and orally available antimalarial drug candidate (P218) that potently inhibits both wild-type and clin. relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of PfDHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant PfDHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development.
- 15Yang, T.; Ottilie, S.; Istvan, E. S.; Godinez-Macias, K. P.; Lukens, A. K.; Baragaña, B.; Campo, B.; Walpole, C.; Niles, J. C.; Chibale, K.; Dechering, K. J.; Llinás, M.; Lee, M. C. S.; Kato, N.; Wyllie, S.; McNamara, C. W.; Gamo, F. J.; Burrows, J.; Fidock, D. A.; Goldberg, D. E.; Gilbert, I. H.; Wirth, D. F.; Winzeler, E. A. MalDA, Accelerating Malaria Drug Discovery. Trends Parasitol. 2021, 37, 493– 507, DOI: 10.1016/j.pt.2021.01.009[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXosVOmur4%253D&md5=7e9ca6289fc74201d9bb49cf32d4aca0Malaria Drug Accelerator, Accelerating Malaria Drug DiscoveryYang, Tuo; Ottilie, Sabine; Istvan, Eva S.; Godinez-Macias, Karla P.; Lukens, Amanda K.; Baragana, Beatriz; Campo, Brice; Walpole, Chris; Niles, Jacquin C.; Chibale, Kelly; Dechering, Koen J.; Llinas, Manuel; Lee, Marcus C. S.; Kato, Nobutaka; Wyllie, Susan; McNamara, Case W.; Gamo, Francisco Javier; Burrows, Jeremy; Fidock, David A.; Goldberg, Daniel E.; Gilbert, Ian H.; Wirth, Dyann F.; Winzeler, Elizabeth A.Trends in Parasitology (2021), 37 (6), 493-507CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)A review. The Malaria Drug Accelerator (MalDA) is a consortium of 15 leading scientific labs. The aim of MalDA is to improve and accelerate the early antimalarial drug discovery process by identifying new, essential, druggable targets. In addn., it seeks to produce early lead inhibitors that may be advanced into drug candidates suitable for preclin. development and subsequent clin. testing in humans. By sharing resources, including expertise, knowledge, materials, and reagents, the consortium strives to eliminate the structural barriers often encountered in the drug discovery process. Here we discuss the mission of the consortium and its scientific achievements, including the identification of new chem. and biol. validated targets, as well as future scientific directions.
- 16Carolino, K.; Winzeler, E. A. The antimalarial resistome - finding new drug targets and their modes of action. Curr. Opin. Microbiol. 2020, 57, 49– 55, DOI: 10.1016/j.mib.2020.06.004[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlaju77I&md5=66b977eedbf79997dbf956b50101c13eThe antimalarial resistome - finding new drug targets and their modes of actionCarolino, Krypton; Winzeler, Elizabeth A.Current Opinion in Microbiology (2020), 57 (), 49-55CODEN: COMIF7; ISSN:1369-5274. (Elsevier Ltd.)A review. To this day, malaria remains a global burden, affecting millions of people, esp. those in sub-Saharan Africa and Asia. The rise of drug resistance to current antimalarial treatments, including artemisinin-based combination therapies, has made discovering new small mol. compds. with novel modes of action an urgent matter. The concerted effort to construct enormous compd. libraries and develop high-throughput phenotypic screening assays to find compds. effective at specifically clearing malaria-causing Plasmodium parasites at any stage of the life cycle has provided many antimalarial prospects, but does not indicate their target or mode of action. Here, we review recent advances in antimalarial drug discovery efforts, focusing on the following 'omics' approaches in mode of action studies: IVIEWGA, CETSA, metabolomic profiling.
- 17Luth, M. R.; Gupta, P.; Ottilie, S.; Winzeler, E. A. Using in Vitro Evolution and Whole Genome Analysis To Discover Next Generation Targets for Antimalarial Drug Discovery. ACS Infect. Dis. 2018, 4, 301– 314, DOI: 10.1021/acsinfecdis.7b00276[ACS Full Text], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivVahu70%253D&md5=3d46f38b82a7c3276832463c5dd29c2cUsing in Vitro Evolution and Whole Genome Analysis To Discover Next Generation Targets for Antimalarial Drug DiscoveryLuth, Madeline R.; Gupta, Purva; Ottilie, Sabine; Winzeler, Elizabeth A.ACS Infectious Diseases (2018), 4 (3), 301-314CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)A review. Although many new anti-infectives have been discovered and developed solely using phenotypic cellular screening and assay optimization, most researchers recognize that structure-guided drug design is more practical and less costly. In addn., a greater chem. space can be interrogated with structure-guided drug design. The practicality of structure-guided drug design has launched a search for the targets of compds. discovered in phenotypic screens. One method that has been used extensively in malaria parasites for target discovery and chem. validation is in vitro evolution and whole genome anal. (IVIEWGA). Here, small mols. from phenotypic screens with demonstrated antiparasitic activity are used in genome-based target discovery methods. In this Review, we discuss the newest, most promising druggable targets discovered or further validated by evolution-based methods, as well as some exceptions.
- 18Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.; Cohen, S. B.; Spencer, K. R.; Gonzalez-Paez, G. E.; Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H.-P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.; Fidock, D. A.; Winzeler, E. A.; Diagana, T. T. Spiroindolones, a potent compound class for the treatment of malaria. Science 2010, 329, 1175– 1180, DOI: 10.1126/science.1193225[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtV2hsr%252FJ&md5=239bc9babd5cb5f07e2be38741038e2cSpiroindolones, a Potent Compound Class for the Treatment of MalariaRottmann, Matthias; McNamara, Case; Yeung, Bryan K. S.; Lee, Marcus C. S.; Zou, Bin; Russell, Bruce; Seitz, Patrick; Plouffe, David M.; Dharia, Neekesh V.; Tan, Jocelyn; Cohen, Steven B.; Spencer, Kathryn R.; Gonzalez-Paez, Gonzalo E.; Lakshminarayana, Suresh B.; Goh, Anne; Suwanarusk, Rossarin; Jegla, Timothy; Schmitt, Esther K.; Beck, Hans-Peter; Brun, Reto; Nosten, Francois; Renia, Laurent; Dartois, Veronique; Keller, Thomas H.; Fidock, David A.; Winzeler, Elizabeth A.; Diagana, Thierry T.Science (Washington, DC, United States) (2010), 329 (5996), 1175-1180CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Recent reports of increased tolerance to artemisinin derivs.-the most recently adopted class of antimalarials-have prompted a need for new treatments. The spirotetrahydro-β-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clin. isolates at low nanomolar concn. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
- 19Baragana, B.; Hallyburton, I.; Lee, M. C. S.; Norcross, N. R.; Grimaldi, R.; Otto, T. D.; Proto, W. R.; Blagborough, A. M.; Meister, S.; Wirjanata, G.; Ruecker, A.; Upton, L. M.; Abraham, T. S.; Almeida, M. J.; Pradhan, A.; Porzelle, A.; Martinez, M. S.; Bolscher, J. M.; Woodland, A.; Luksch, T.; Norval, S.; Zuccotto, F.; Thomas, J.; Simeons, F.; Stojanovski, L.; Osuna-Cabello, M.; Brock, P. M.; Churcher, T. S.; Sala, K. A.; Zakutansky, S. E.; Jimenez-Diaz, M. B.; Sanz, L. M.; Riley, J.; Basak, R.; Campbell, M.; Avery, V. M.; Sauerwein, R. W.; Dechering, K. J.; Noviyanti, R.; Campo, B.; Frearson, J. A.; Angulo-Barturen, I.; Ferrer-Bazaga, S.; Gamo, F. J.; Wyatt, P. G.; Leroy, D.; Siegl, P.; Delves, M. J.; Kyle, D. E.; Wittlin, S.; Marfurt, J.; Price, R. N.; Sinden, R. E.; Winzeler, E. A.; Charman, S. A.; Bebrevska, L.; Gray, D. W.; Campbell, S.; Fairlamb, A. H.; Willis, P. A.; Rayner, J. C.; Fidock, D. A.; Read, K. D.; Gilbert, I. H. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature 2015, 522, 315– 320, DOI: 10.1038/nature14451[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFeiurzE&md5=bd5f1dd3c4389aa8a6f193df0aa068a1A novel multiple-stage antimalarial agent that inhibits protein synthesisBaragana, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martinez, Maria Santos; Bolscher, Judith M.; Woodland, Andrew; Luksch, Torsten; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jimenez-Diaz, Maria Belen; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W.; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Inigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth A.; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul A.; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.Nature (London, United Kingdom) (2015), 522 (7556), 315-320CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compd. with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clin. needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening program against blood-stage malaria parasites; its mol. target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
- 20Corpas-Lopez, V.; Moniz, S.; Thomas, M.; Wall, R. J.; Torrie, L. S.; Zander-Dinse, D.; Tinti, M.; Brand, S.; Stojanovski, L.; Manthri, S.; Hallyburton, I.; Zuccotto, F.; Wyatt, P. G.; De Rycker, M.; Horn, D.; Ferguson, M. A. J.; Clos, J.; Read, K. D.; Fairlamb, A. H.; Gilbert, I. H.; Wyllie, S. Pharmacological Validation of N-Myristoyltransferase as a Drug Target in Leishmania donovani. ACS Infect. Dis. 2019, 5, 111– 122, DOI: 10.1021/acsinfecdis.8b00226[ACS Full Text], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVCisb%252FI&md5=5901cad939de2eb6beab6d4454e21acbPharmacological Validation of N-Myristoyltransferase as a Drug Target in Leishmania donovaniCorpas-Lopez, Victoriano; Moniz, Sonia; Thomas, Michael; Wall, Richard J.; Torrie, Leah S.; Zander-Dinse, Dorothea; Tinti, Michele; Brand, Stephen; Stojanovski, Laste; Manthri, Sujatha; Hallyburton, Irene; Zuccotto, Fabio; Wyatt, Paul G.; De Rycker, Manu; Horn, David; Ferguson, Michael A. J.; Clos, Joachim; Read, Kevin D.; Fairlamb, Alan H.; Gilbert, Ian H.; Wyllie, SusanACS Infectious Diseases (2019), 5 (1), 111-122CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and L. infantum, is responsible for ∼30,000 deaths annually. Available treatments are inadequate, and there is a pressing need for new therapeutics. N-Myristoyltransferase (NMT) remains one of the few genetically validated drug targets in these parasites. Here, the authors sought to pharmacol. validate this enzyme in Leishmania. A focused set of 1600 pyrazolyl sulfonamide compds. was screened against L. major NMT in a robust high-throughput biochem. assay. Several potent inhibitors were identified with marginal selectivity over the human enzyme. There was little correlation between the enzyme potency of these inhibitors and their cellular activity against L. donovani axenic amastigotes, and this discrepancy could be due to poor cellular uptake due to the basicity of these compds. Thus, a series of analogs were synthesized with less basic centers. Although most of these compds. continued to suffer from relatively poor antileishmanial activity, the authors' most potent inhibitor of LmNMT (DDD100097, Ki of 0.34 nM) showed modest activity against L. donovani intracellular amastigotes (EC50 of 2.4 μM) and maintained a modest therapeutic window over the human enzyme. Two unbiased approaches, namely, screening against the authors' cosmid-based overexpression library and thermal proteome profiling (TPP), confirm that DDD100097 (compd. 2) acts on-target within parasites. Oral dosing with compd. 2 resulted in a 52% redn. in parasite burden in the authors' mouse model of VL. Thus, NMT is now a pharmacol. validated target in Leishmania. The challenge in finding drug candidates remains to identify alternative strategies to address the drop-off in activity between enzyme inhibition and in vitro activity while maintaining sufficient selectivity over the human enzyme, both issues that continue to plague studies in this area.
- 21Hoepfner, D.; McNamara, C. W.; Lim, C. S.; Studer, C.; Riedl, R.; Aust, T.; McCormack, S. L.; Plouffe, D. M.; Meister, S.; Schuierer, S.; Plikat, U.; Hartmann, N.; Staedtler, F.; Cotesta, S.; Schmitt, E. K.; Petersen, F.; Supek, F.; Glynne, R. J.; Tallarico, J. A.; Porter, J. A.; Fishman, M. C.; Bodenreider, C.; Diagana, T. T.; Movva, N. R.; Winzeler, E. A. Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin. Cell Host Microbe 2012, 11, 654– 663, DOI: 10.1016/j.chom.2012.04.015[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XosFChtbk%253D&md5=ed482a3e7abcbf027f4223d45bdeebd8Selective and specific inhibition of the Plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporinHoepfner, Dominic; McNamara, Case W.; Lim, Chek Shik; Studer, Christian; Riedl, Ralph; Aust, Thomas; McCormack, Susan L.; Plouffe, David M.; Meister, Stephan; Schuierer, Sven; Plikat, Uwe; Hartmann, Nicole; Staedtler, Frank; Cotesta, Simona; Schmitt, Esther K.; Petersen, Frank; Supek, Frantisek; Glynne, Richard J.; Tallarico, John A.; Porter, Jeffrey A.; Fishman, Mark C.; Bodenreider, Christophe; Diagana, Thierry T.; Movva, N. Rao; Winzeler, Elizabeth A.Cell Host & Microbe (2012), 11 (6), 654-663CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)With renewed calls for malaria eradication, next-generation antimalarials need be active against drug-resistant parasites and efficacious against both liver- and blood-stage infections. The authors screened a natural product library to identify inhibitors of Plasmodium falciparum blood and liver stage proliferation. Cladosporin, a fungal secondary metabolite whose target and mechanism of action are not known for any species, was identified as having potent, nanomolar, antiparasitic activity against both blood and liver stages. Using postgenomic methods, including a yeast deletion strains collection, the authors show that cladosporin specifically inhibits protein synthesis by directly targeting P. falciparum cytosolic lysyl-tRNA synthetase. Further, cladosporin is >100-fold more potent against parasite lysyl-tRNA synthetase relative to the human enzyme, which is conferred by the identity of two amino acids within the enzyme active site. The data indicate that lysyl-tRNA synthetase is an attractive, druggable, antimalarial target that can be selectively inhibited.
- 22Kato, N.; Comer, E.; Sakata-Kato, T.; Sharma, A.; Sharma, M.; Maetani, M.; Bastien, J.; Brancucci, N. M.; Bittker, J. A.; Corey, V.; Clarke, D.; Derbyshire, E. R.; Dornan, G. L.; Duffy, S.; Eckley, S.; Itoe, M. A.; Koolen, K. M. J.; Lewis, T. A.; Lui, P. S.; Lukens, A. K.; Lund, E.; March, S.; Meibalan, E.; Meier, B. C.; McPhail, J. A.; Mitasev, B.; Moss, E. L.; Sayes, M.; Van Gessel, Y.; Wawer, M. J.; Yoshinaga, T.; Zeeman, A.-M.; Avery, V. M.; Bhatia, S. N.; Burke, J. E.; Catteruccia, F.; Clardy, J. C.; Clemons, P. A.; Dechering, K. J.; Duvall, J. R.; Foley, M. A.; Gusovsky, F.; Kocken, C. H. M.; Marti, M.; Morningstar, M. L.; Munoz, B.; Neafsey, D. E.; Sharma, A.; Winzeler, E. A.; Wirth, D. F.; Scherer, C. A.; Schreiber, S. L. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature 2016, 538, 344– 349, DOI: 10.1038/nature19804[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslWhsLrI&md5=68e6e2018f2d49278d255ee02bfc8d16Diversity-oriented synthesis yields novel multistage antimalarial inhibitorsKato, Nobutaka; Comer, Eamon; Sakata-Kato, Tomoyo; Sharma, Arvind; Sharma, Manmohan; Maetani, Micah; Bastien, Jessica; Brancucci, Nicolas M.; Bittker, Joshua A.; Corey, Victoria; Clarke, David; Derbyshire, Emily R.; Dornan, Gillian L.; Duffy, Sandra; Eckley, Sean; Itoe, Maurice A.; Koolen, Karin M. J.; Lewis, Timothy A.; Lui, Ping S.; Lukens, Amanda K.; Lund, Emily; March, Sandra; Meibalan, Elamaran; Meier, Bennett C.; McPhail, Jacob A.; Mitasev, Branko; Moss, Eli L.; Sayes, Morgane; Van Gessel, Yvonne; Wawer, Mathias J.; Yoshinaga, Takashi; Zeeman, Anne-Marie; Avery, Vicky M.; Bhatia, Sangeeta N.; Burke, John E.; Catteruccia, Flaminia; Clardy, Jon C.; Clemons, Paul A.; Dechering, Koen J.; Duvall, Jeremy R.; Foley, Michael A.; Gusovsky, Fabian; Kocken, Clemens H. M.; Marti, Matthias; Morningstar, Marshall L.; Munoz, Benito; Neafsey, Daniel E.; Sharma, Amit; Winzeler, Elizabeth A.; Wirth, Dyann F.; Scherer, Christina A.; Schreiber, Stuart L.Nature (London, United Kingdom) (2016), 538 (7625), 344-349CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compds. Here the authors investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compds. that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. The authors report the identification of such compds. with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These mols. are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. The authors' findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.
- 23Herman, J. D.; Pepper, L. R.; Cortese, J. F.; Estiu, G.; Galinsky, K.; Zuzarte-Luis, V.; Derbyshire, E. R.; Ribacke, U.; Lukens, A. K.; Santos, S. A.; Patel, V.; Clish, C. B.; Sullivan, W. J., Jr.; Zhou, H.; Bopp, S. E.; Schimmel, P.; Lindquist, S.; Clardy, J.; Mota, M. M.; Keller, T. L.; Whitman, M.; Wiest, O.; Wirth, D. F.; Mazitschek, R. The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Sci. Transl. Med. 2015, 7, 288ra77, DOI: 10.1126/scitranslmed.aaa3575
- 24Gilbert, I. H. Drug discovery for neglected diseases: Molecular target-based and phenotypic approaches. J. Med. Chem. 2013, 56, 7719– 7726, DOI: 10.1021/jm400362b[ACS Full Text], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVWkur%252FF&md5=dcc54f2ed7987c3089bbe4944b747420Drug Discovery for Neglected Diseases: Molecular Target-Based and Phenotypic ApproachesGilbert, Ian H.Journal of Medicinal Chemistry (2013), 56 (20), 7719-7726CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Drug discovery for neglected tropical diseases is carried out using both target-based and phenotypic approaches. In this paper, target-based approaches are discussed, with a particular focus on human African trypanosomiasis. Target-based drug discovery can be successful, but careful selection of targets is required. There are still very few fully validated drug targets in neglected diseases, and there is a high attrition rate in target-based drug discovery for these diseases. Phenotypic screening is a powerful method in both neglected and non-neglected diseases and has been very successfully used. Identification of mol. targets from phenotypic approaches can be a way to identify potential new drug targets.
- 25Frearson, J. A.; Wyatt, P. G.; Gilbert, I. H.; Fairlamb, A. H. Target assessment for antiparasitic drug discovery. Trends Parasitol. 2007, 23, 589– 595, DOI: 10.1016/j.pt.2007.08.019[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVSktrzJ&md5=40edb0aa482e5b6155dc653397c1c45dTarget assessment for antiparasitic drug discoveryFrearson, Julie A.; Wyatt, Paul G.; Gilbert, Ian H.; Fairlamb, Alan H.Trends in Parasitology (2007), 23 (12), 589-595CODEN: TPRACT; ISSN:1471-4922. (Elsevier B.V.)A review. Drug discovery is a high-risk, expensive and lengthy process taking at least 12 years and costing upwards of US$500 million per drug to reach the clinic. For neglected diseases, the drug discovery process is driven by medical need and guided by pre-defined target product profiles. Assessment and prioritization of the most promising targets for entry into screening programs is crucial for maximizing the chances of success. Here, we describe criteria used in our drug discovery unit for target assessment and introduce the 'traffic-light' system as a prioritization and management tool. We hope this brief review will stimulate basic scientists to acquire addnl. information necessary for drug discovery.
- 26Gilbert, I. H. Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matter. Parasitology 2014, 141, 28– 36, DOI: 10.1017/S0031182013001017[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sfotlSqtQ%253D%253D&md5=0a069387de0bdc08edc20951a27452d9Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matterGilbert Ian HParasitology (2014), 141 (1), 28-36 ISSN:.Target-based approaches for human African trypanosomiasis (HAT) and related parasites can be a valuable route for drug discovery for these diseases. However, care needs to be taken in selection of both the actual drug target and the chemical matter that is developed. In this article, potential criteria to aid target selection are described. Then the physiochemical properties of typical oral drugs are discussed and compared to those of known anti-parasitics.
- 27Wyatt, P. G.; Gilbert, I. H.; Read, K. D.; Fairlamb, A. H. Target Validation: Linking Target and Chemical Properties to Desired Product Profile. Curr. Top. Med. Chem. 2011, 11, 1275– 1283, DOI: 10.2174/156802611795429185[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnt1Cnsb4%253D&md5=ad865a1eb11fc8f175be5aba2866028dTarget validation: linking target and chemical properties to desired product profileWyatt, Paul G.; Gilbert, Ian H.; Read, Kevin D.; Fairlamb, Alan H.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2011), 11 (10), 1275-1283CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. The discovery of drugs is a lengthy, high-risk and expensive business taking at least 12 years and is estd. to cost upwards of US$800 million for each drug to be successfully approved for clin. use. Much of this cost is driven by the late phase clin. trials and therefore the ability to terminate early those projects destined to fail is paramount to prevent unwanted costs and wasted effort. Although neglected diseases drug discovery is driven more by unmet medical need rather than financial considerations, the need to minimize wasted money and resources is even more vital in this under-funded area. To ensure any drug discovery project is addressing the requirements of the patients and health care providers and delivering a benefit over existing therapies, the ideal attributes of a novel drug needs to be pre-defined by a set of criteria called a target product profile. Using a target product profile the drug discovery process, clin. study design, and compd. characteristics can be defined all the way back through to the suitability or druggability of the intended biochem. target. Assessment and prioritization of the most promising targets for entry into screening programs is crucial for maximizing chances of success.
- 28Chaparro, M. J.; Calderón, F.; Castañeda, P.; Fernández-Alvaro, E.; Gabarró, R.; Gamo, F. J.; Gómez-Lorenzo, M. G.; Martín, J.; Fernández, E. Efforts Aimed To Reduce Attrition in Antimalarial Drug Discovery: A Systematic Evaluation of the Current Antimalarial Targets Portfolio. ACS Infect. Dis. 2018, 4, 568– 576, DOI: 10.1021/acsinfecdis.7b00211[ACS Full Text], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmt1Wktg%253D%253D&md5=1ddb89e0ebe4b40b54d1ecc097ad40c5Efforts Aimed To Reduce Attrition in Antimalarial Drug Discovery: A Systematic Evaluation of the Current Antimalarial Targets PortfolioChaparro, Maria Jesus; Calderon, Felix; Castaneda, Pablo; Fernandez-Alvaro, Elena; Gabarro, Raquel; Gamo, Francisco Javier; Gomez-Lorenzo, Maria G.; Martin, Julio; Fernandez, EstherACS Infectious Diseases (2018), 4 (4), 568-576CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and more than 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (artemisinin combination therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes of action, able to relieve symptoms as fast as the artemisinins and/or block malaria transmission. During the past few years, the antimalarial community has focused their efforts on phenotypic screening as a pragmatic approach to identify new hits. Optimization efforts on several chem. series have been successful, and clin. candidates have been identified. In addn., recent advances in genetics and proteomics have led to the target deconvolution of phenotypic clin. candidates. New mechanisms of action will also be crit. to overcome resistance and reduce attrition. Therefore, a complementary strategy focused on identifying well-validated targets to start hit identification programs is essential to reinforce the clin. pipeline. Leveraging published data, the authors have assessed the status quo of the current antimalarial target portfolio with a focus on the blood stage clin. disease. From an extensive list of reported Plasmodium targets, the authors have defined triage criteria. These criteria consider genetic, pharmacol., and chem. validation, as well as tractability/doability, and safety implications. These criteria have provided a quant. score that has led the authors to prioritize those targets with the highest probability to deliver successful and differentiated new drugs.
- 29Gashaw, I.; Ellinghaus, P.; Sommer, A.; Asadullah, K. What makes a good drug target?. Drug Discovery Today 2011, 16, 1037– 1043, DOI: 10.1016/j.drudis.2011.09.007[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFCqs73K&md5=e95c90b75d4797df0230253a3c34d7edWhat makes a good drug target?Gashaw, Isabella; Ellinghaus, Peter; Sommer, Anette; Asadullah, KhusruDrug Discovery Today (2011), 16 (23/24), 1037-1043CODEN: DDTOFS; ISSN:1359-6446. (Elsevier B.V.)A review. Novel therapeutics in areas with a high unmet medical need are based on innovative drug targets. Although biologicals' have enlarged the space of druggable mols., the no. of appropriate drug targets is still limited. Discovering and assessing the potential therapeutic benefit of a drug target is based not only on exptl., mechanistic and pharmacol. studies but also on a theor. mol. druggability assessment, an early evaluation of potential side effects and considerations regarding opportunities for commercialization. This article defines key properties of a good drug target from the perspective of a pharmaceutical company.
- 30Nasamu, A. S.; Falla, A.; Pasaje, C. F. A.; Wall, B. A.; Wagner, J. C.; Ganesan, S. M.; Goldfless, S. J.; Niles, J. C. An integrated platform for genome engineering and gene expression perturbation in Plasmodium falciparum. Sci. Rep. 2021, 11, 342, DOI: 10.1038/s41598-020-77644-4[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtF2qt7k%253D&md5=347bfa9260e2fe7648f2c985ce5d8dcaAn integrated platform for genome engineering and gene expression perturbation in Plasmodium falciparumNasamu, Armiyaw S.; Falla, Alejandra; Pasaje, Charisse Flerida A.; Wall, Bridget A.; Wagner, Jeffrey C.; Ganesan, Suresh M.; Goldfless, Stephen J.; Niles, Jacquin C.Scientific Reports (2021), 11 (1), 342CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)Establishing robust genome engineering methods in the malarial parasite, Plasmodium falciparum, has the potential to substantially improve the efficiency with which we gain understanding of this pathogen's biol. to propel treatment and elimination efforts. Methods for manipulating gene expression and engineering the P. falciparum genome have been validated. However, a significant barrier to fully leveraging these advances is the difficulty assocd. with assembling the extremely high AT content DNA constructs required for modifying the P. falciparum genome. These are frequently unstable in commonly-used circular plasmids. We address this bottleneck by devising a DNA assembly framework leveraging the improved reliability with which large AT-rich regions can be efficiently manipulated in linear plasmids. This framework integrates several key functional genetics outcomes via CRISPR/Cas9 and other methods from a common, validated framework. Overall, this mol. toolkit enables P. falciparum genetics broadly and facilitates deeper interrogation of parasite genes involved in diverse biol. processes.
- 31Ganesan, S. M.; Falla, A.; Goldfless, S. J.; Nasamu, A. S.; Niles, J. C. Synthetic RNA-protein modules integrated with native translation mechanisms to control gene expression in malaria parasites. Nat. Commun. 2016, 7, 10727, DOI: 10.1038/ncomms10727[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsVaruro%253D&md5=67a9f9b62eaa8fc7c802a10c0ce0b13cSynthetic RNA-protein modules integrated with native translation mechanisms to control gene expression in malaria parasitesGanesan, Suresh M.; Falla, Alejandra; Goldfless, Stephen J.; Nasamu, Armiyaw S.; Niles, Jacquin C.Nature Communications (2016), 7 (), 10727CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)Synthetic posttranscriptional regulation of gene expression is important for understanding fundamental biol. and programming new cellular processes in synthetic biol. Previous strategies for regulating translation in eukaryotes have focused on disrupting individual steps in translation, including initiation and mRNA cleavage. In emphasizing modularity and cross-organism functionality, these systems are designed to operate orthogonally to native control mechanisms. Here we introduce a broadly applicable strategy for robustly controlling protein translation by integrating synthetic translational control via a small-mol.-regulated RNA-protein module with native mechanisms that simultaneously regulate multiple facets of cellular RNA fate. We demonstrate that this strategy reduces 'leakiness' to improve overall expression dynamic range, and can be implemented without sacrificing modularity and cross-organism functionality. We illustrate this in Saccharomyces cerevisiae and the non-model human malarial parasite, Plasmodium falciparum. Given the limited functional genetics toolkit available for P. falciparum, we establish the utility of this strategy for defining essential genes.
- 32Pisa, R.; Kapoor, T. M. Chemical strategies to overcome resistance against targeted anticancer therapeutics. Nat. Chem. Biol. 2020, 16, 817– 825, DOI: 10.1038/s41589-020-0596-8[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVagsr%252FI&md5=e660ceac1742d78cae3670710ad5731fChemical strategies to overcome resistance against targeted anticancer therapeuticsPisa, Rudolf; Kapoor, Tarun M.Nature Chemical Biology (2020), 16 (8), 817-825CODEN: NCBABT; ISSN:1552-4450. (Nature Research)Abstr.: Emergence of resistance is a major factor limiting the efficacy of molecularly targeted anticancer drugs. Understanding the specific mutations, or other genetic or cellular changes, that confer drug resistance can help in the development of therapeutic strategies with improved efficacies. Here, we outline recent progress in understanding chemotype-specific mechanisms of resistance and present chem. strategies, such as designing drugs with distinct binding modes or using proteolysis targeting chimeras, to overcome resistance. We also discuss how targeting multiple binding sites with bifunctional inhibitors or identifying collateral sensitivity profiles can be exploited to limit the emergence of resistance. Finally, we highlight how incorporating analyses of resistance early in drug development can help with the design and evaluation of therapeutics that can have long-term benefits for patients. [graphic not available: see fulltext].
- 33Zhang, M.; Wang, C.; Otto, T. D.; Oberstaller, J.; Liao, X.; Adapa, S. R.; Udenze, K.; Bronner, I. F.; Casandra, D.; Mayho, M.; Brown, J.; Li, S.; Swanson, J.; Rayner, J. C.; Jiang, R. H. Y.; Adams, J. H. Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis. Science 2018, 360, eaap7847, DOI: 10.1126/science.aap7847
- 34Bushell, E.; Gomes, A. R.; Sanderson, T.; Anar, B.; Girling, G.; Herd, C.; Metcalf, T.; Modrzynska, K.; Schwach, F.; Martin, R. E.; Mather, M. W.; McFadden, G. I.; Parts, L.; Rutledge, G. G.; Vaidya, A. B.; Wengelnik, K.; Rayner, J. C.; Billker, O. Functional profiling of a Plasmodium genome reveals an abundance of essential genes. Cell 2017, 170, 260– 272, DOI: 10.1016/j.cell.2017.06.030[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFygtbzN&md5=c7745367d9db0a8112aa59f7fb9ebe70Functional profiling of a plasmodium genome reveals an abundance of essential genesBushell, Ellen; Gomes, Ana Rita; Sanderson, Theo; Anar, Burcu; Girling, Gareth; Herd, Colin; Metcalf, Tom; Modrzynska, Katarzyna; Schwach, Frank; Martin, Rowena E.; Mather, Michael W.; McFadden, Geoffrey I.; Parts, Leopold; Rutledge, Gavin G.; Vaidya, Akhil B.; Wengelnik, Kai; Rayner, Julian C.; Billker, OliverCell (Cambridge, MA, United States) (2017), 170 (2), 260-272.e8CODEN: CELLB5; ISSN:0092-8674. (Cell Press)The genomes of malaria parasites contain many genes of unknown function. To assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2578 barcoded Plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. At a single stage of its complex life cycle, P. berghei requires two-thirds of genes for optimal growth, the highest proportion reported from any organism and a probable consequence of functional optimization necessitated by genomic redns. during the evolution of parasitism. In contrast, extreme functional redundancy has evolved among expanded gene families operating at the parasite-host interface. The level of genetic redundancy in a single-celled organism may thus reflect the degree of environmental variation it experiences. In the case of Plasmodium parasites, this helps rationalize both the relative successes of drugs and the greater difficulty of making an effective vaccine.
- 35Ding, X. C.; Ubben, D.; Wells, T. N. A framework for assessing the risk of resistance for anti-malarials in development. Malar. J. 2012, 11, 292, DOI: 10.1186/1475-2875-11-292[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bgsVagtQ%253D%253D&md5=69e59ccb7d2a87dad485437582ae09d0A framework for assessing the risk of resistance for anti-malarials in developmentDing Xavier C; Ubben David; Wells Timothy N CMalaria journal (2012), 11 (), 292 ISSN:.Resistance is a constant challenge for anti-infective drug development. Since they kill sensitive organisms, anti-infective agents are bound to exert an evolutionary pressure toward the emergence and spread of resistance mechanisms, if such resistance can arise by stochastic mutation events. New classes of medicines under development must be designed or selected to stay ahead in this vicious circle of resistance control. This involves both circumventing existing resistance mechanisms and selecting molecules which are resilient against the development and spread of resistance. Cell-based screening methods have led to a renaissance of new classes of anti-malarial medicines, offering us the potential to select and modify molecules based on their resistance potential. To that end, a standardized in vitro methodology to assess quantitatively these characteristics in Plasmodium falciparum during the early phases of the drug development process has been developed and is presented here. It allows the identification of anti-malarial compounds with overt resistance risks and the prioritization of the most robust ones. The integration of this strategy in later stages of development, registration, and deployment is also discussed.
- 36Duffey, M.; Blasco, B.; Burrows, J. N.; Wells, T. N. C.; Fidock, D.; Leroy, D. Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials. Trends Parasitol. 2021, 37, 709– 721, DOI: 10.1016/j.pt.2021.04.006[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXht1Git77J&md5=e31d7cac81ad93ef9e9709bac2741202Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarialsDuffey, Maelle; Blasco, Benjamin; Burrows, Jeremy N.; Wells, Timothy N. C.; Fidock, David A.; Leroy, DidierTrends in Parasitology (2021), 37 (8), 709-721CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)A review. Strategies to counteract or prevent emerging drug resistance are crucial for the design of next-generation antimalarials. In the past, resistant parasites were generally identified following treatment failures in patients, and compds. would have to be abandoned late in development. An early understanding of how candidate therapeutics lose efficacy as parasites evolve resistance is important to facilitate drug design and improve resistance detection and monitoring up to the postregistration phase. We describe a new strategy to assess resistance to antimalarial compds. as early as possible in preclin. development by leveraging tools to define the Plasmodium falciparum resistome, predict potential resistance risks of clin. failure for candidate therapeutics, and inform decisions to guide antimalarial drug development.
- 37Ahouidi, A.; Ali, M.; Almagro-Garcia, J.; Amambua-Ngwa, A.; Amaratunga, C.; Amato, R.; Amenga-Etego, L.; Andagalu, B.; Anderson, T.; Andrianaranjaka, V.; Apinjoh, T.; Ariani, C.; Ashley, E.; Auburn, S.; Awandare, G.; Ba, H.; Baraka, V.; Barry, A.; Bejon, P.; Bertin, G.; Boni, M.; Borrmann, S.; Bousema, T.; Branch, O.; Bull, P.; Busby, G.; Chookajorn, T.; Chotivanich, K.; Claessens, A.; Conway, D.; Craig, A.; D’Alessandro, U.; Dama, S.; Day, N.; Denis, B.; Diakite, M.; DjimdÈ, A.; Dolecek, C.; Dondorp, A.; Drakeley, C.; Drury, E.; Duffy, P.; Echeverry, D.; Egwang, T.; Erko, B.; Fairhurst, R.; Faiz, A.; Fanello, C.; Fukuda, M.; Gamboa, D.; Ghansah, A.; Golassa, L.; Goncalves, S.; Hamilton, W.; Harrison, G.; Hart, L.; Henrichs, C.; Hien, T.; Hill, C.; Hodgson, A.; Hubbart, C.; Imwong, M.; Ishengoma, D.; Jackson, S.; Jacob, C.; Jeffery, B.; Jeffreys, A.; Johnson, K.; Jyothi, D.; Kamaliddin, C.; Kamau, E.; Kekre, M.; Kluczynski, K.; Kochakarn, T.; KonatÈ, A.; Kwiatkowski, D.; Kyaw, M.; Lim, P.; Lon, C.; Loua, K.; MaÔga-AscofarÈ, O.; Malangone, C.; Manske, M.; Marfurt, J.; Marsh, K.; Mayxay, M.; Miles, A.; Miotto, O.; Mobegi, V.; Mokuolu, O.; Montgomery, J.; Mueller, I.; Newton, P.; Nguyen, T.; Nguyen, T.; Noedl, H.; Nosten, F.; Noviyanti, R.; Nzila, A.; Ochola-Oyier, L.; Ocholla, H.; Oduro, A.; Omedo, I.; Onyamboko, M.; Ouedraogo, J.; Oyebola, K.; Pearson, R.; Peshu, N.; Phyo, A.; Plowe, C.; Price, R.; Pukrittayakamee, S.; Randrianarivelojosia, M.; Rayner, J.; Ringwald, P.; Rockett, K.; Rowlands, K.; Ruiz, L.; Saunders, D.; Shayo, A.; Siba, P.; Simpson, V.; Stalker, J.; Su, X.; Sutherland, C.; Takala-Harrison, S.; Tavul, L.; Thathy, V.; Tshefu, A.; Verra, F.; Vinetz, J.; Wellems, T.; Wendler, J.; White, N.; Wright, I.; Yavo, W.; Ye, H. An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples. Wellcome Open Res. 2021, 6, 16168, DOI: 10.12688/wellcomeopenres.16168.2
- 38Leeson, P. D. Molecular inflation, attrition and the rule of five. Adv. Drug Delivery Rev. 2016, 101, 22– 33, DOI: 10.1016/j.addr.2016.01.018[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFCrt7k%253D&md5=7e31a4390c28a0f203f2254bcfb754afMolecular inflation, attrition and the rule of fiveLeeson, Paul D.Advanced Drug Delivery Reviews (2016), 101 (), 22-33CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Physicochem. properties underlie all aspects of drug action and are crit. for soly., permeability and successful formulation. Specific physicochem. properties shown to be relevant to oral drugs are size, lipophilicity, ionisation, hydrogen bonding, polarity, aromaticity and shape. The rule of 5 (Ro5) and subsequent studies have raised awareness of the importance of compd. quality amongst bioactive mols. Lipophilicity, probably the most important phys. property of oral drugs, has on av. changed little over time in oral drugs, until increases in drugs published after 1990. In contrast other mol. properties such as av. size have increased significantly. Factors influencing property inflation include the targets pursued, where antivirals frequently violate the Ro5, risk/benefit considerations, and variable drug discovery practices. The compds. published in patents from the pharmaceutical industry are on av. larger, more lipophilic and less complex than marketed oral drugs. The variation between individual companies' patented compds. is due to different practices and not to the targets pursued. Overall, there is demonstrable phys. property attrition in moving from patents to candidate drugs to marketed drugs. The pharmaceutical industry's recent poor productivity has been due, in part, to progression of mols. that are unable to unambiguously test clin. efficacy, and attrition can therefore be improved by ensuring candidate drug quality is 'fit for purpose.' The combined ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of many marketed drugs are optimized relative to other mols. acting at the same target. Application of LLE in optimization can help identify improved leads, even with challenging targets that seem to require lipophilic ligands. Because of their targets, some projects may need to pursue 'beyond Ro5' physicochem. space; such projects will require non-std. lead generation and optimization and should not dominate in a well-balanced portfolio. Compd. quality is controllable by lead selection and optimization and should not be a cause of clin. failure.
- 39Leeson, P. D.; Young, R. J. Molecular Property Design: Does Everyone Get It?. ACS Med. Chem. Lett. 2015, 6, 722– 725, DOI: 10.1021/acsmedchemlett.5b00157[ACS Full Text], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptVGksr4%253D&md5=5a807a8d049ce8cf4adc186891a9234dMolecular Property Design: Does Everyone Get It?Leeson, Paul D.; Young, Robert J.ACS Medicinal Chemistry Letters (2015), 6 (7), 722-725CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A review. The principles of mol. property optimization in drug design have been understood for decades, yet much drug discovery activity today is conducted at the periphery of historical druglike property space. Lead optimization trajectories aimed at reducing physicochem. risk, assisted by ligand efficiency metrics, could help to reduce clin. attrition rates.
- 40Young, R. J.; Leeson, P. D. Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations. J. Med. Chem. 2018, 61, 6421– 6467, DOI: 10.1021/acs.jmedchem.8b00180[ACS Full Text], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXntVCmu7Y%253D&md5=f040ef02d161e070bb5021fde1585e66Mapping the Efficiency and Physicochemical Trajectories of Successful OptimizationsYoung, Robert J.; Leeson, Paul D.Journal of Medicinal Chemistry (2018), 61 (15), 6421-6467CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The practices and tactics employed in successful optimizations are examd., judged from the trajectories of ligand efficiency and property evolution. A wide range of targets is analyzed, encompassing a variety of hit finding methods (HTS, fragments, encoded library technol.) and types of mols., including those beyond the rule of five. The wider employment of efficiency metrics and lipophilicity control is evident in contemporary practice and the impact on quality demonstrable. What is clear is that while targets are different, successful mols. are almost invariably among the most efficient for their target, even at the extremes. Trajectory mapping, based on principles rather than rules, is useful in assessing quality and progress in optimizations while benchmarking against competitors and assessing property-dependent risks.
- 41Agoni, C.; Olotu, F. A.; Ramharack, P.; Soliman, M. E. Druggability and drug-likeness concepts in drug design: are biomodelling and predictive tools having their say?. J. Mol. Model 2020, 26, 120, DOI: 10.1007/s00894-020-04385-6[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXptVGrt7w%253D&md5=41203c0c37710955e899391bf0baf38cDruggability and drug-likeness concepts in drug design: are biomodelling and predictive tools having their say?Agoni, Clement; Olotu, Fisayo A.; Ramharack, Pritika; Soliman, Mahmoud E.Journal of Molecular Modeling (2020), 26 (6), 120CODEN: JMMOFK; ISSN:0948-5023. (Springer)A review. Abstr.: The drug discovery process typically involves target identification and design of suitable drug mols. against these targets. Despite decades of exptl. investigations in the drug discovery domain, about 96% overall failure rate has been recorded in drug development due to the "undruggability" of various identified disease targets, in addn. to other challenges. Likewise, the high attrition rate of drug candidates in the drug discovery process has also become an enormous challenge for the pharmaceutical industry. To alleviate this neg. outlook, new trends in drug discovery have emerged. By drifting away from exptl. research methods, computational tools and big data are becoming valuable in the prediction of biol. target druggability and the drug-likeness of potential therapeutic agents. These tools have proven to be useful in saving time and reducing research costs. As with any emerging technique, however, controversial opinions have been presented regarding the validation of predictive computational tools. To address the challenges assocd. with these varying opinions, this review attempts to highlight the principles of druggability and drug-likeness and their recent advancements in the drug discovery field. Herein, we present the different computational tools and their reliability of predictive anal. in the drug discovery domain. We believe that this report would serve as a comprehensive guide towards computational-oriented drug discovery research. Graphical abstractHighlights of methods for assessing the druggability of biol. targets [graphic not available: see fulltext].
- 42Favuzza, P.; de Lera Ruiz, M.; Thompson, J. K.; Triglia, T.; Ngo, A.; Steel, R. W. J.; Vavrek, M.; Christensen, J.; Healer, J.; Boyce, C.; Guo, Z.; Hu, M.; Khan, T.; Murgolo, N.; Zhao, L.; Penington, J. S.; Reaksudsan, K.; Jarman, K.; Dietrich, M. H.; Richardson, L.; Guo, K. Y.; Lopaticki, S.; Tham, W. H.; Rottmann, M.; Papenfuss, T.; Robbins, J. A.; Boddey, J. A.; Sleebs, B. E.; Sabroux, H. J.; McCauley, J. A.; Olsen, D. B.; Cowman, A. F. Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle. Cell Host Microbe 2020, 27, 642– 658, DOI: 10.1016/j.chom.2020.02.005[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXktlarsrc%253D&md5=c54719d969f0e82bb5e91a7ae9176e7aDual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life CycleFavuzza, Paola; de Lera Ruiz, Manuel; Thompson, Jennifer K.; Triglia, Tony; Ngo, Anna; Steel, Ryan W. J.; Vavrek, Marissa; Christensen, Janni; Healer, Julie; Boyce, Christopher; Guo, Zhuyan; Hu, Mengwei; Khan, Tanweer; Murgolo, Nicholas; Zhao, Lianyun; Penington, Jocelyn Sietsma; Reaksudsan, Kitsanapong; Jarman, Kate; Dietrich, Melanie H.; Richardson, Lachlan; Guo, Kai-Yuan; Lopaticki, Sash; Tham, Wai-Hong; Rottmann, Matthias; Papenfuss, Tony; Robbins, Jonathan A.; Boddey, Justin A.; Sleebs, Brad E.; Sabroux, Helene Jousset; McCauley, John A.; Olsen, David B.; Cowman, Alan F.Cell Host & Microbe (2020), 27 (4), 642-658.e12CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addn., WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.
- 43De Rycker, M.; Baragana, B.; Duce, S. L.; Gilbert, I. H. Challenges and recent progress in drug discovery for tropical diseases. Nature 2018, 559, 498– 506, DOI: 10.1038/s41586-018-0327-4[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtl2jt7zP&md5=3bc57ce68776462cf6a053efa276a989Challenges and recent progress in drug discovery for tropical diseasesDe Rycker, Manu; Baragana, Beatriz; Duce, Suzanne L.; Gilbert, Ian H.Nature (London, United Kingdom) (2018), 559 (7715), 498-506CODEN: NATUAS; ISSN:0028-0836. (Nature Research)Infectious tropical diseases have a huge effect in terms of mortality and morbidity, and impose a heavy economic burden on affected countries. These diseases predominantly affect the world's poorest people. Currently available drugs are inadequate for the majority of these diseases, and there is an urgent need for new treatments. This Review discusses some of the challenges involved in developing new drugs to treat these diseases and highlights recent progress. While there have been notable successes, there is still a long way to go.
- 44Alam, M. M.; Sanchez-Azqueta, A.; Janha, O.; Flannery, E. L.; Mahindra, A.; Mapesa, K.; Char, A. B.; Sriranganadane, D.; Brancucci, N. M. B.; Antonova-Koch, Y.; Crouch, K.; Simwela, N. V.; Millar, S. B.; Akinwale, J.; Mitcheson, D.; Solyakov, L.; Dudek, K.; Jones, C.; Zapatero, C.; Doerig, C.; Nwakanma, D. C.; Vázquez, M. J.; Colmenarejo, G.; Lafuente-Monasterio, M. J.; Leon, M. L.; Godoi, P. H. C.; Elkins, J. M.; Waters, A. P.; Jamieson, A. G.; Álvaro, E. F.; Ranford-Cartwright, L. C.; Marti, M.; Winzeler, E. A.; Gamo, F. J.; Tobin, A. B. Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target. Science 2019, 365, eaau1682, DOI: 10.1126/science.aau1682
- 45Schalkwijk, J.; Allman, E. L.; Jansen, P. A. M.; de Vries, L. E.; Verhoef, J. M. J.; Jackowski, S.; Botman, P. N. M.; Beuckens-Schortinghuis, C. A.; Koolen, K. M. J.; Bolscher, J. M.; Vos, M. W.; Miller, K.; Reeves, S. A.; Pett, H.; Trevitt, G.; Wittlin, S.; Scheurer, C.; Sax, S.; Fischli, C.; Angulo-Barturen, I.; Jiménez-Diaz, M. B.; Josling, G.; Kooij, T. W. A.; Bonnert, R.; Campo, B.; Blaauw, R. H.; Rutjes, F.; Sauerwein, R. W.; Llinás, M.; Hermkens, P. H. H.; Dechering, K. J. Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum. Sci. Transl. Med. 2019, 11, eaas9917, DOI: 10.1126/scitranslmed.aas9917
- 46Summers, R. L.; Pasaje, C. F. A.; Pisco, J. P.; Striepen, J.; Luth, M. R.; Kumpornsin, K.; Carpenter, E. F.; Munro, J. T.; Lin, D.; Plater, A.; Punekar, A. S.; Shepherd, A. M.; Shepherd, S. M.; Vanaerschot, M.; Murithi, J. M.; Rubiano, K.; Akidil, A.; Ottilie, S.; Mittal, N.; Dilmore, A. H.; Won, M.; Mandt, R. E. K.; McGowen, K.; Owen, E.; Walpole, C.; Llinás, M.; Lee, M. C. S.; Winzeler, E. A.; Fidock, D. A.; Gilbert, I. H.; Wirth, D. F.; Niles, J. C.; Baragaña, B.; Lukens, A. K. Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention. Cell Chem. Biol. 2021, DOI: 10.1016/j.chembiol.2021.07.010
- 47Koselny, K.; Green, J.; Favazzo, L.; Glazier, V. E.; DiDone, L.; Ransford, S.; Krysan, D. J. Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase. ACS Infect. Dis. 2016, 2, 268– 280, DOI: 10.1021/acsinfecdis.5b00134[ACS Full Text], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivFOmur4%253D&md5=7cbbf24d6b9d80867c4a66dea648e750Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA SynthetaseKoselny, Kristy; Green, Julianne; Favazzo, Lacey; Glazier, Virginia E.; DiDone, Louis; Ransford, Shea; Krysan, Damian J.ACS Infectious Diseases (2016), 2 (4), 268-280CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)AR-12/OSU-03012 is an antitumor celecoxib-deriv. that has progressed to Phase I clin. trial as an anticancer agent and has activity against a no. of infectious agents including fungi, bacteria and viruses. However, the mechanism of these activities has remained unclear. Based on a chem.-genetic profiling approach in yeast, we have found that AR-12 is an ATP-competitive, time-dependent inhibitor of yeast acetyl CoA synthetase. AR-12-treated fungal cells show phenotypes consistent with the genetic redn. of acetyl CoA synthetase activity, including induction of autophagy, decreased histone acetylation, and loss of cellular integrity. In addn., AR-12 is a weak inhibitor of human acetyl CoA synthetase ACCS2. Acetyl CoA synthetase activity is essential in many fungi and parasites. In contrast, acetyl CoA is primarily synthesized by an alternate enzyme, ATP-citrate lyase, in mammalian cells. Taken together, our results indicate that AR-12 is a non-nucleoside acetyl CoA synthetase inhibitor and that acetyl CoA synthetase may be a feasible antifungal drug target.
- 48Gisselberg, J. E.; Herrera, Z.; Orchard, L. M.; Llinás, M.; Yeh, E. Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding Site. Cell Chem. Biol. 2018, 25, 185– 193, DOI: 10.1016/j.chembiol.2017.11.010[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVehtL3M&md5=ca3af32ced2ff0c07551e08932766858Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding SiteGisselberg, Jolyn E.; Herrera, Zachary; Orchard, Lindsey M.; Llinas, Manuel; Yeh, EllenCell Chemical Biology (2018), 25 (2), 185-193.e5CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)The bifunctional farnesyl/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key branchpoint enzyme in isoprenoid biosynthesis in Plasmodium falciparum (malaria) parasites. PfFPPS/GGPPS is a validated, high-priority antimalarial drug target. Unfortunately, current bisphosphonate drugs that inhibit FPPS and GGPPS enzymes by acting as a diphosphate substrate analog show poor bioavailability and selectivity for PfFPPS/GGPPS. We identified a new non-bisphosphonate compd., MMV019313, which is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes of inhibition. Mol. docking indicated that MMV019313 did not bind previously characterized substrate sites in PfFPPS/GGPPS. Our finding uncovers a new, selective small-mol. binding site in this important antimalarial drug target with superior druggability compared with the known inhibitor site and sets the stage for the development of Plasmodium-specific FPPS/GGPPS inhibitors.
- 49Jordão, F. M.; Gabriel, H. B.; Alves, J. M.; Angeli, C. B.; Bifano, T. D.; Breda, A.; de Azevedo, M. F.; Basso, L. A.; Wunderlich, G.; Kimura, E. A.; Katzin, A. M. Cloning and characterization of bifunctional enzyme farnesyl diphosphate/geranylgeranyl diphosphate synthase from Plasmodium falciparum. Malar. J. 2013, 12, 184, DOI: 10.1186/1475-2875-12-184[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVejtr7K&md5=536a7f8b59fbce904afeea70e3ab03baCloning and characterization of bifunctional enzyme farnesyl diphosphate/geranylgeranyl diphosphate synthase from Plasmodium falciparumJordao, Fabiana M.; Gabriel, Heloisa B.; Alves, Joao M. P.; Angeli, Claudia B.; Bifano, Thais D.; Breda, Ardala; de Azevedo, Mauro F.; Basso, Luiz A.; Wunderlich, Gerhard; Kimura, Emilia A.; Katzin, Alejandro M.Malaria Journal (2013), 12 (), 184CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)Background: Isoprenoids are the most diverse and abundant group of natural products. In Plasmodium falciparum, isoprenoid synthesis proceeds through the Me erythritol diphosphate pathway and the products are further metabolized by farnesyl diphosphate synthase (FPPS), turning this enzyme into a key branch point of the isoprenoid synthesis. Changes in FPPS activity could alter the flux of isoprenoid compds. downstream of FPPS and, hence, play a central role in the regulation of a no. of essential functions in Plasmodium parasites. Methods: The isolation and cloning of gene PF3D7_18400 was done by amplification from cDNA from mixed stage parasites of P. falciparum. After sequencing, the fragment was subcloned in pGEX2T for recombinant protein expression. To verify if the PF3D7_1128400 gene encodes a functional rPfFPPS protein, its catalytic activity was assessed using the substrate [4-14C] isopentenyl diphosphate and three different allylic substrates: dimethylallyl diphosphate, geranyl diphosphate or farnesyl diphosphate. The reaction products were identified by thin layer chromatog. and reverse phase high-performance liq. chromatog. To confirm the product spectrum formed of rPfFPPS, isoprenic compds. were also identified by mass spectrometry. Apparent kinetic consts. KM and Vmax for each substrate were detd. by Michaelis-Menten; also, inhibition assays were performed using risedronate. Results: The expressed protein of P. falciparum FPPS (rPfFPPS) catalyzes the synthesis of farnesyl diphosphate, as well as geranylgeranyl diphosphate, being therefore a bifunctional FPPS/geranylgeranyl diphosphate synthase (GGPPS) enzyme. The apparent KM values for the substrates dimethylallyl diphosphate, geranyl diphosphate and farnesyl diphosphate were, resp., 68 ± 5 μM, 7.8 ± 1.3 μM and 2.06 ± 0.4 μM. The protein is expressed constitutively in all intra-erythrocytic stages of P. falciparum, demonstrated by using transgenic parasites with a haemagglutinin-tagged version of FPPS. Also, the present data demonstrate that the recombinant protein is inhibited by risedronate. Conclusions: The rPfFPPS is a bifunctional FPPS/GGPPS enzyme and the structure of products FOH and GGOH were confirmed mass spectrometry. Plasmodial FPPS represents a potential target for the rational design of chemotherapeutic agents to treat malaria.
- 50Yoo, E.; Schulze, C. J.; Stokes, B. H.; Onguka, O.; Yeo, T.; Mok, S.; Gnädig, N. F.; Zhou, Y.; Kurita, K.; Foe, I. T.; Terrell, S. M.; Boucher, M. J.; Cieplak, P.; Kumpornsin, K.; Lee, M. C. S.; Linington, R. G.; Long, J. Z.; Uhlemann, A. C.; Weerapana, E.; Fidock, D. A.; Bogyo, M. The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites. Cell Chem. Biol. 2020, 27, 143– 157, DOI: 10.1016/j.chembiol.2020.01.001[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFyitb0%253D&md5=236485f5855092e9e7e2acde4d3b9ac4The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum ParasitesYoo, Euna; Schulze, Christopher J.; Stokes, Barbara H.; Onguka, Ouma; Yeo, Tomas; Mok, Sachel; Gnadig, Nina F.; Zhou, Yani; Kurita, Kenji; Foe, Ian T.; Terrell, Stephanie M.; Boucher, Michael J.; Cieplak, Piotr; Kumpornsin, Krittikorn; Lee, Marcus C. S.; Linington, Roger G.; Long, Jonathan Z.; Uhlemann, Anne-Catrin; Weerapana, Eranthie; Fidock, David A.; Bogyo, MatthewCell Chemical Biology (2020), 27 (2), 143-157.e5CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homol. to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metab. Resistance selections yielded parasites that showed only minor redns. in sensitivity and that acquired mutations in a PRELI domain-contg. protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets.
- 51Schulze, C. J.; Navarro, G.; Ebert, D.; DeRisi, J.; Linington, R. G. Salinipostins A-K, long-chain bicyclic phosphotriesters as a potent and selective antimalarial chemotype. J. Org. Chem. 2015, 80, 1312– 20, DOI: 10.1021/jo5024409[ACS Full Text], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosVCktw%253D%253D&md5=83525e8326d755cd99f9bc90a072305cSalinipostins A-K, Long-Chain Bicyclic Phosphotriesters as a Potent and Selective Antimalarial ChemotypeSchulze, Christopher J.; Navarro, Gabriel; Ebert, Daniel; DeRisi, Joseph; Linington, Roger G.Journal of Organic Chemistry (2015), 80 (3), 1312-1320CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Despite significant advances in antimalarial chemotherapy over the past 30 years, development of resistance to frontline drugs remains a significant challenge that limits efforts to eradicate the disease. We now report the discovery of a new class of antimalarials, salinipostins A-K, with low nanomolar potencies and high selectivity indexes against mammalian cells (salinipostin A: Plasmodium falciparum EC50 50 nM, HEK293T cytotoxicity EC50 > 50 μM). These compds. were isolated from a marine-derived Salinospora sp. bacterium and contain a bicyclic phosphotriester core structure, which is a rare motif among natural products. This scaffold differs significantly from the structures of known antimalarial compds. and represents a new lead structure for the development of therapeutic targets in malaria. Examn. of the growth stage specificity of salinipostin A indicates that it exhibits growth stage-specific effects that differ from compds. that inhibit heme polymn., while resistance selection expts. were unable to identify parasite populations that exhibited significant resistance against this compd. class.
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- 53Wong, C. H.; Siah, K. W.; Lo, A. W. Estimation of clinical trial success rates and related parameters. Biostatistics 2019, 20, 273– 286, DOI: 10.1093/biostatistics/kxx069[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mvmslejsw%253D%253D&md5=95204fe37aec420da08b3401189e3ba5Estimation of clinical trial success rates and related parametersWong Chi Heem; Siah Kien Wei; Lo Andrew WBiostatistics (Oxford, England) (2019), 20 (2), 273-286 ISSN:.Previous estimates of drug development success rates rely on relatively small samples from databases curated by the pharmaceutical industry and are subject to potential selection biases. Using a sample of 406 038 entries of clinical trial data for over 21 143 compounds from January 1, 2000 to October 31, 2015, we estimate aggregate clinical trial success rates and durations. We also compute disaggregated estimates across several trial features including disease type, clinical phase, industry or academic sponsor, biomarker presence, lead indication status, and time. In several cases, our results differ significantly in detail from widely cited statistics. For example, oncology has a 3.4% success rate in our sample vs. 5.1% in prior studies. However, after declining to 1.7% in 2012, this rate has improved to 2.5% and 8.3% in 2014 and 2015, respectively. In addition, trials that use biomarkers in patient-selection have higher overall success probabilities than trials without biomarkers.
- 54Wang, J.; Yazdani, S.; Han, A.; Schapira, M. Structure-based view of the druggable genome. Drug Discovery Today 2020, 25, 561– 567, DOI: 10.1016/j.drudis.2020.02.006[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjs12rtbo%253D&md5=7c85eee4b0bb92e0801ea781c067cd9aStructure-based view of the druggable genomeWang, Jiayan; Yazdani, Setayesh; Han, Ana; Schapira, MatthieuDrug Discovery Today (2020), 25 (3), 561-567CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. International efforts are underway to develop chem. probes for specific protein families, and a 'Target 2035' call to expand these efforts towards a comprehensive chem. coverage of the druggable human genome was recently announced. But what is the druggable genome. Here, we systematically review structures of proteins bound to drug-like ligands available from the Protein Data Bank (PDB) and use ligand desolvation upon binding as a druggability metric to draw a landscape of the human druggable genome. The vast majority of druggable protein families, including some highly populated and disease-assocd. families, are almost orphan of small-mol. ligands. We propose a list of 46 druggable domains representing 3440 human proteins that could be the focus of large chem. probe discovery efforts.
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- 57Jomaa, H.; Wiesner, J.; Sanderbrand, S.; Altincicek, B.; Weidemeyer, C.; Hintz, M.; Turbachova, I.; Eberl, M.; Zeidler, J.; Lichtenthaler, H. K.; Soldati, D.; Beck, E. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 1999, 285, 1573– 1576, DOI: 10.1126/science.285.5433.1573[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXlslOqsrY%253D&md5=3b12e27cdd89da3155de8099c725f3b9Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugsJomaa, Hassan; Wiesner, Jochen; Sanderbrand, Silke; Altincicek, Boran; Weidemeyer, Claus; Hintz, Martin; Turbachova, Ivana; Eberl, Matthias; Zeidler, Johannes; Lichtenthaler, Hartmut K.; Soldati, Dominique; Beck, EwaldScience (Washington, D. C.) (1999), 285 (5433), 1573-1576CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A mevalonate-independent pathway of isoprenoid biosynthesis present in Plasmodium falciparum was shown to represent an effective target for chemotherapy of malaria. This pathway includes 1-deoxy-D-xylulose 5-phosphate (DOXP) as a key metabolite. The presence of two genes encoding the enzymes DOXP synthase and DOXP reductoisomerase suggests that isoprenoid biosynthesis in P. falciparum depends on the DOXP pathway. This pathway is probably located in the apicoplast. The recombinant P. falciparum DOXP reductoisomerase was inhibited by fosmidomycin and its deriv., FR-900098. Both drugs suppressed the in vitro growth of multidrug-resistant P. falciparum strains. After therapy with these drugs, mice infected with the rodent malaria parasite P. vinckei were cured.
- 58Yeh, E.; DeRisi, J. L. Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum. PLoS Biol. 2011, 9, e1001138, DOI: 10.1371/journal.pbio.1001138[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1WrtLbN&md5=7495d8087b18cba682c62077eabda432Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparumYeh, Ellen; DeRisi, Joseph L.PLoS Biology (2011), 9 (8), e1001138CODEN: PBLIBG; ISSN:1545-7885. (Public Library of Science)Plasmodium spp. parasites harbor an unusual plastid organelle called the apicoplast. Due to its prokaryotic origin and essential function, the apicoplast is a key target for development of new anti-malarials. Over 500 proteins are predicted to localize to this organelle and several prokaryotic biochem. pathways have been annotated, yet the essential role of the apicoplast during human infection remains a mystery. Previous work showed that treatment with fosmidomycin, an inhibitor of non-mevalonate isoprenoid precursor biosynthesis in the apicoplast, inhibits the growth of blood-stage P. falciparum. Here, the authors demonstrate that fosmidomycin inhibition can be chem. rescued by supplementation with isopentenyl pyrophosphate (IPP), the pathway product. Surprisingly, IPP supplementation also completely reverses death following treatment with antibiotics that cause loss of the apicoplast. Antibiotic-treated parasites rescued with IPP over multiple cycles specifically lose their apicoplast genome and fail to process or localize organelle proteins, rendering them functionally apicoplast-minus. Despite the loss of this essential organelle, these apicoplast-minus auxotrophs can be grown indefinitely in asexual blood stage culture but are entirely dependent on exogenous IPP for survival. These findings indicate that isoprenoid precursor biosynthesis is the only essential function of the apicoplast during blood-stage growth. Moreover, apicoplast-minus P. falciparum strains will be a powerful tool for further investigation of apicoplast biol. as well as drug and vaccine development.
- 59Uddin, T.; McFadden, G. I.; Goodman, C. D. Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites. Antimicrob. Agents Chemother. 2018, 62, e01161-17, DOI: 10.1128/AAC.01161-17
- 60Yu, M.; Kumar, T. R.; Nkrumah, L. J.; Coppi, A.; Retzlaff, S.; Li, C. D.; Kelly, B. J.; Moura, P. A.; Lakshmanan, V.; Freundlich, J. S.; Valderramos, J. C.; Vilcheze, C.; Siedner, M.; Tsai, J. H.; Falkard, B.; Sidhu, A. B.; Purcell, L. A.; Gratraud, P.; Kremer, L.; Waters, A. P.; Schiehser, G.; Jacobus, D. P.; Janse, C. J.; Ager, A.; Jacobs, W. R., Jr.; Sacchettini, J. C.; Heussler, V.; Sinnis, P.; Fidock, D. A. The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites. Cell Host Microbe 2008, 4, 567– 78, DOI: 10.1016/j.chom.2008.11.001[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlKqtQ%253D%253D&md5=8166213984c5cfc1589764054c68e43cThe fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasitesYu, Min; Kumar, T. R. Santha; Nkrumah, Louis J.; Coppi, Alida; Retzlaff, Silke; Li, Celeste D.; Kelly, Brendan J.; Moura, Pedro A.; Lakshmanan, Viswanathan; Freundlich, Joel S.; Valderramos, Juan-Carlos; Vilcheze, Catherine; Siedner, Mark; Tsai, Jennifer H.-C.; Falkard, Brie; Sidhu, Amar bir Singh; Purcell, Lisa A.; Gratraud, Paul; Kremer, Laurent; Waters, Andrew P.; Schiehser, Guy; Jacobus, David P.; Janse, Chris J.; Ager, Arba; Jacobs, William R., Jr.; Sacchettini, James C.; Heussler, Volker; Sinnis, Photini; Fidock, David A.Cell Host & Microbe (2008), 4 (6), 567-578CODEN: CHMECB; ISSN:1931-3128. (Cell Press)The fatty acid synthesis type II pathway has received considerable interest as a candidate therapeutic target in Plasmodium falciparum asexual blood-stage infections. This apicoplast-resident pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chem. and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial FabI. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood-stage growth. In contrast, mosquito-derived, FabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver-stage development in vitro. This defect is characterized by an inability to form intrahepatic merosomes that normally initiate blood-stage infections. These data illuminate key differences between liver- and blood-stage parasites in their requirements for host vs. de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions.
- 61Vaughan, A. M.; O’Neill, M. T.; Tarun, A. S.; Camargo, N.; Phuong, T. M.; Aly, A. S.; Cowman, A. F.; Kappe, S. H. Type II fatty acid synthesis is essential only for malaria parasite late liver stage development. Cell. Microbiol. 2009, 11, 506– 520, DOI: 10.1111/j.1462-5822.2008.01270.x[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXivVejsrg%253D&md5=f2b83d0fe99674f0ae4e721a7a0a8f8dType II fatty acid synthesis is essential only for malaria parasite late liver stage developmentVaughan, Ashley M.; O'Neill, Matthew T.; Tarun, Alice S.; Camargo, Nelly; Phuong, Thuan M.; Aly, Ahmed S. I.; Cowman, Alan F.; Kappe, Stefan H. I.Cellular Microbiology (2009), 11 (3), 506-520CODEN: CEMIF5; ISSN:1462-5814. (Wiley-Blackwell)Intracellular malaria parasites require lipids for growth and replication. They possess a prokaryotic type II fatty acid synthesis (FAS II) pathway that localizes to the apicoplast plastid organelle and is assumed to be necessary for pathogenic blood stage replication. However, the importance of FAS II throughout the complex parasite life cycle remains unknown. We show in a rodent malaria model that FAS II enzymes localize to the sporozoite and liver stage apicoplast. Targeted deletion of FabB/F, a crit. enzyme in fatty acid synthesis, did not affect parasite blood stage replication, mosquito stage development and initial infection in the liver. This was confirmed by knockout of FabZ, another crit. FAS II enzyme. However, FAS II-deficient Plasmodium yoelii liver stages failed to form exo-erythrocytic merozoites, the invasive stage that first initiates blood stage infection. Furthermore, deletion of FabI in the human malaria parasite Plasmodium falciparum did not show a redn. in asexual blood stage replication in vitro. Malaria parasites therefore depend on the intrinsic FAS II pathway only at one specific life cycle transition point, from liver to blood.
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Abstract
Figure 1
Figure 1. Geographical location of MalDA consortium members. MalDA, with its state-of-the-art Plasmodium-adapted technology platforms in bioinformatics, chemo-informatics, chemo-proteomics, genetic manipulation, metabolomics, in vivo resistance evaluation, and medicinal chemistry expertise, is at the forefront of the antimalarial drug discovery process by providing tools to accelerate the finding of new starting points for drug discovery (www.malariaDA.org). (15)
Figure 2
Figure 2. Current MalDA target portfolio
Figure 3
Figure 3. Structures of tool compounds (see text for references to each structure)
Figure 4
Figure 4. (A) Analysis of the P. falciparum genome categorizing targets according to their predicted essentiality, druggability, and the presence of mammalian orthologs. The number of proteins in each category is shown in parentheses. (B) Analysis of high value targets, according to tool compounds, the presence of mammalian orthologs, and proof of concept in humans. The number of proteins in each category is shown in parentheses. Where there is only one protein in a category, it is stated explicitly. Most MalDA targets fall into the light blue or violet regions.
References
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- 6Dembélé, L.; Franetich, J.-F.; Lorthiois, A.; Gego, A.; Zeeman, A.-M.; Kocken, C. H. M.; Le Grand, R.; Dereuddre-Bosquet, N.; van Gemert, G.-J.; Sauerwein, R.; Vaillant, J.-C.; Hannoun, L.; Fuchter, M. J.; Diagana, T. T.; Malmquist, N. A.; Scherf, A.; Snounou, G.; Mazier, D. Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures. Nat. Med. 2014, 20, 307– 312, DOI: 10.1038/nm.3461[Crossref], [PubMed], [CAS], Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFaqt7w%253D&md5=80fad73cf8a19f15df33e949540f02f7Persistence and activation of malaria hypnozoites in long-term primary hepatocyte culturesDembele, Laurent; Franetich, Jean-Francois; Lorthiois, Audrey; Gego, Audrey; Zeeman, Anne-Marie; Kocken, Clemens H. M.; Le Grand, Roger; Dereuddre-Bosquet, Nathalie; van Gemert, Geert-Jan; Sauerwein, Robert; Vaillant, Jean-Christophe; Hannoun, Laurent; Fuchter, Matthew J.; Diagana, Thierry T.; Malmquist, Nicholas A.; Scherf, Artur; Snounou, Georges; Mazier, DominiqueNature Medicine (New York, NY, United States) (2014), 20 (3), 307-312CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)Malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of Plasmodium vivax and Plasmodium ovale, hinder global efforts to control and eliminate malaria. As primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. Currently, analyses of hypnozoites, including screening of compds. that would eliminate them, can only be made using common macaque models, principally Macaca rhesus and Macaca fascicularis, exptl. infected with the relapsing Plasmodium cynomolgi. Here, we present a protocol for long-term in vitro cultivation of P. cynomolgi-infected M. fascicularis primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept expt., we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation. The protocol presented may further enable investigations of hypnozoite biol. and the search for compds. that kill hypnozoites or disrupt their quiescence.
- 7Barrett, M. P.; Kyle, D. E.; Sibley, L. D.; Radke, J. B.; Tarleton, R. L. Protozoan persister-like cells and drug treatment failure. Nat. Rev. Microbiol. 2019, 17, 607– 620, DOI: 10.1038/s41579-019-0238-x[Crossref], [PubMed], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1eksLfO&md5=0a1415d70f7d0c420666c5999854f51cProtozoan persister-like cells and drug treatment failureBarrett, Michael P.; Kyle, Dennis E.; Sibley, L. David; Radke, Joshua B.; Tarleton, Rick L.Nature Reviews Microbiology (2019), 17 (10), 607-620CODEN: NRMACK; ISSN:1740-1526. (Nature Research)Antimicrobial treatment failure threatens our ability to control infections. In addn. to antimicrobial resistance, treatment failures are increasingly understood to derive from cells that survive drug treatment without selection of genetically heritable mutations. Parasitic protozoa, such as Plasmodium species that cause malaria, Toxoplasma gondii and kinetoplastid protozoa, including Trypanosoma cruzi and Leishmania spp., cause millions of deaths globally. These organisms can evolve drug resistance and they also exhibit phenotypic diversity, including the formation of quiescent or dormant forms that contribute to the establishment of long-term infections that are refractory to drug treatment, which we refer to as 'persister-like cells'. In this Review, we discuss protozoan persister-like cells that have been linked to persistent infections and discuss their impact on therapeutic outcomes following drug treatment.
- 8Abraham, M.; Gagaring, K.; Martino, M. L.; Vanaerschot, M.; Plouffe, D. M.; Calla, J.; Godinez-Macias, K. P.; Du, A. Y.; Wree, M.; Antonova-Koch, Y.; Eribez, K.; Luth, M. R.; Ottilie, S.; Fidock, D. A.; McNamara, C. W.; Winzeler, E. A. Probing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation Antimalarials. ACS Infect. Dis. 2020, 6, 613– 628, DOI: 10.1021/acsinfecdis.9b00482[ACS Full Text], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjsVOmsLY%253D&md5=6ee44448c30e2dff0d6707d8a7ad3d1aProbing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation AntimalarialsAbraham, Matthew; Gagaring, Kerstin; Martino, Marisa L.; Vanaerschot, Manu; Plouffe, David M.; Calla, Jaeson; Godinez-Macias, Karla P.; Du, Alan Y.; Wree, Melanie; Antonova-Koch, Yevgeniya; Eribez, Korina; Luth, Madeline R.; Ottilie, Sabine; Fidock, David A.; McNamara, Case W.; Winzeler, Elizabeth A.ACS Infectious Diseases (2020), 6 (4), 613-628CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)Most phenotypic screens aiming to discover new antimalarial chemotypes begin with low cost, high-throughput tests against the asexual blood stage (ABS) of the malaria parasite life cycle. Compds. active against the ABS are then sequentially tested in more difficult assays that predict whether a compd. has other beneficial attributes. Although applying this strategy to new chem. libraries may yield new leads, repeated iterations may lead to diminishing returns and the rediscovery of chemotypes hitting well-known targets. Here, we adopted a different strategy to find starting points, testing ∼70,000 open source small mols. from the Global Health Chem. Diversity Library for activity against the liver stage, mature sexual stage, and asexual blood stage malaria parasites in parallel. In addn., instead of using an asexual assay that measures accumulated parasite DNA in the presence of compd. (SYBR green), a real time luciferase-dependent parasite viability assay was used that distinguishes slow-acting (delayed death) from fast-acting compds. Among 382 scaffolds with the activity confirmed by dose response (<10 μM), we discovered 68 novel delayed-death, 84 liver stage, and 68 stage V gametocyte inhibitors as well. Although 89% of the evaluated compds. had activity in only a single life cycle stage, we discovered six potent (half-maximal inhibitory concn. of <1 μM) multistage scaffolds, including a novel cytochrome bc1 chemotype. Our data further show the luciferase-based assays have higher sensitivity. Chemoinformatic anal. of pos. and neg. compds. identified scaffold families with a strong enrichment for activity against specific or multiple stages.
- 9Antonova-Koch, Y.; Meister, S.; Abraham, M.; Luth, M. R.; Ottilie, S.; Lukens, A. K.; Sakata-Kato, T.; Vanaerschot, M.; Owen, E.; Jado, J. C.; Maher, S. P.; Calla, J.; Plouffe, D.; Zhong, Y.; Chen, K.; Chaumeau, V.; Conway, A. J.; McNamara, C. W.; Ibanez, M.; Gagaring, K.; Serrano, F. N.; Eribez, K.; Taggard, C. M.; Cheung, A. L.; Lincoln, C.; Ambachew, B.; Rouillier, M.; Siegel, D.; Nosten, F.; Kyle, D. E.; Gamo, F.-J.; Zhou, Y.; Llinás, M.; Fidock, D. A.; Wirth, D. F.; Burrows, J.; Campo, B.; Winzeler, E. A. Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. Science 2018, 362, eaat9446, DOI: 10.1126/science.aat9446
- 10Gamo, F. J.; Sanz, L. M.; Vidal, J.; de Cozar, C.; Alvarez, E.; Lavandera, J. L.; Vanderwall, D. E.; Green, D. V.; Kumar, V.; Hasan, S.; Brown, J. R.; Peishoff, C. E.; Cardon, L. R.; Garcia-Bustos, J. F. Thousands of chemical starting points for antimalarial lead identification. Nature 2010, 465, 305– 310, DOI: 10.1038/nature09107[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmt1Ois7k%253D&md5=a1fd8c0b89a5650ecba31f5456928b42Thousands of chemical starting points for antimalarial lead identificationGamo, Francisco-Javier; Sanz, Laura M.; Vidal, Jaume; de Cozar, Cristina; Alvarez, Emilio; Lavandera, Jose-Luis; Vanderwall, Dana E.; Green, Darren V. S.; Kumar, Vinod; Hasan, Samiul; Brown, James R.; Peishoff, Catherine E.; Cardon, Lon R.; Garcia-Bustos, Jose F.Nature (London, United Kingdom) (2010), 465 (7296), 305-310CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chem. class of antimalarials has been introduced into clin. practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compds. in GlaxoSmithKline's chem. library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 μM concn. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compds. originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chem. structures and assocd. data are hereby made public to encourage addnl. drug lead identification efforts and further research into this disease.
- 11Plouffe, D. M.; Wree, M.; Du, A. Y.; Meister, S.; Li, F.; Patra, K.; Lubar, A.; Okitsu, S. L.; Flannery, E. L.; Kato, N.; Tanaseichuk, O.; Comer, E.; Zhou, B.; Kuhen, K.; Zhou, Y.; Leroy, D.; Schreiber, S. L.; Scherer, C. A.; Vinetz, J.; Winzeler, E. A. High-Throughput Assay and Discovery of Small Molecules that Interrupt Malaria Transmission. Cell Host Microbe 2016, 19, 114– 126, DOI: 10.1016/j.chom.2015.12.001[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlKrsQ%253D%253D&md5=297ed2ccee9f8fc5fc2024f2fecffae0High-Throughput Assay and Discovery of Small Molecules that Interrupt Malaria TransmissionPlouffe, David M.; Wree, Melanie; Du, Alan Y.; Meister, Stephan; Li, Fengwu; Patra, Kailash; Lubar, Aristea; Okitsu, Shinji L.; Flannery, Erika L.; Kato, Nobutaka; Tanaseichuk, Olga; Comer, Eamon; Zhou, Bin; Kuhen, Kelli; Zhou, Yingyao; Leroy, Didier; Schreiber, Stuart L.; Scherer, Christina A.; Vinetz, Joseph; Winzeler, Elizabeth A.Cell Host & Microbe (2016), 19 (1), 114-126CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)Preventing transmission is an important element of malaria control. However, most of the current available methods to assay for malaria transmission blocking are relatively low throughput and cannot be applied to large chem. libraries. We have developed a high-throughput and cost-effective assay, the Saponin-lysis Sexual Stage Assay (SaLSSA), for identifying small mols. with transmission-blocking capacity. SaLSSA anal. of 13,983 unique compds. uncovered that >90% of well-characterized antimalarials, including endoperoxides and 4-aminoquinolines, as well as compds. active against asexual blood stages, lost most of their killing activity when parasites developed into metabolically quiescent stage V gametocytes. On the other hand, we identified compds. with consistent low nanomolar transmission-blocking activity, some of which showed cross-reactivity against asexual blood and liver stages. The data clearly emphasize substantial physiol. differences between sexual and asexual parasites and provide a tool and starting points for the discovery and development of transmission-blocking drugs.
- 12Van Voorhis, W. C.; Adams, J. H.; Adelfio, R.; Ahyong, V.; Akabas, M. H.; Alano, P.; Alday, A.; Alemán Resto, Y.; Alsibaee, A.; Alzualde, A.; Andrews, K. T.; Avery, S. V.; Avery, V. M.; Ayong, L.; Baker, M.; Baker, S.; Ben Mamoun, C.; Bhatia, S.; Bickle, Q.; Bounaadja, L.; Bowling, T.; Bosch, J.; Boucher, L. E.; Boyom, F. F.; Brea, J.; Brennan, M.; Burton, A.; Caffrey, C. R.; Camarda, G.; Carrasquilla, M.; Carter, D.; Belen Cassera, M.; Chih-Chien Cheng, K.; Chindaudomsate, W.; Chubb, A.; Colon, B. L.; Colón-López, D. D.; Corbett, Y.; Crowther, G. J.; Cowan, N.; D’Alessandro, S.; Le Dang, N.; Delves, M.; DeRisi, J. L.; Du, A. Y.; Duffy, S.; Abd El-Salam El-Sayed, S.; Ferdig, M. T.; Fernández Robledo, J. A.; Fidock, D. A.; Florent, I.; Fokou, P. V. T.; Galstian, A.; Gamo, F. J.; Gokool, S.; Gold, B.; Golub, T.; Goldgof, G. M.; Guha, R.; Guiguemde, W. A.; Gural, N.; Guy, R. K.; Hansen, M. A. E.; Hanson, K. K.; Hemphill, A.; Hooft van Huijsduijnen, R.; Horii, T.; Horrocks, P.; Hughes, T. B.; Huston, C.; Igarashi, I.; Ingram-Sieber, K.; Itoe, M. A.; Jadhav, A.; Naranuntarat Jensen, A.; Jensen, L. T.; Jiang, R. H. Y.; Kaiser, A.; Keiser, J.; Ketas, T.; Kicka, S.; Kim, S.; Kirk, K.; Kumar, V. P.; Kyle, D. E.; Lafuente, M. J.; Landfear, S.; Lee, N.; Lee, S.; Lehane, A. M.; Li, F.; Little, D.; Liu, L.; Llinás, M.; Loza, M. I.; Lubar, A.; Lucantoni, L.; Lucet, I.; Maes, L.; Mancama, D.; Mansour, N. R.; March, S.; McGowan, S.; Medina Vera, I.; Meister, S.; Mercer, L.; Mestres, J.; Mfopa, A. N.; Misra, R. N.; Moon, S.; Moore, J. P.; Morais Rodrigues da Costa, F.; Müller, J.; Muriana, A.; Nakazawa Hewitt, S.; Nare, B.; Nathan, C.; Narraidoo, N.; Nawaratna, S.; Ojo, K. K.; Ortiz, D.; Panic, G.; Papadatos, G.; Parapini, S.; Patra, K.; Pham, N.; Prats, S.; Plouffe, D. M.; Poulsen, S.-A.; Pradhan, A.; Quevedo, C.; Quinn, R. J.; Rice, C. A.; Abdo Rizk, M.; Ruecker, A.; St. Onge, R.; Salgado Ferreira, R.; Samra, J.; Robinett, N. G.; Schlecht, U.; Schmitt, M.; Silva Villela, F.; Silvestrini, F.; Sinden, R.; Smith, D. A.; Soldati, T.; Spitzmüller, A.; Stamm, S. M.; Sullivan, D. J.; Sullivan, W.; Suresh, S.; Suzuki, B. M.; Suzuki, Y.; Swamidass, S. J.; Taramelli, D.; Tchokouaha, L. R. Y.; Theron, A.; Thomas, D.; Tonissen, K. F.; Townson, S.; Tripathi, A. K.; Trofimov, V.; Udenze, K. O.; Ullah, I.; Vallieres, C.; Vigil, E.; Vinetz, J. M.; Voong Vinh, P.; Vu, H.; Watanabe, N.-a.; Weatherby, K.; White, P. M.; Wilks, A. F.; Winzeler, E. A.; Wojcik, E.; Wree, M.; Wu, W.; Yokoyama, N.; Zollo, P. H. A.; Abla, N.; Blasco, B.; Burrows, J.; Laleu, B.; Leroy, D.; Spangenberg, T.; Wells, T.; Willis, P. A. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. PLoS Pathog. 2016, 12, e1005763, DOI: 10.1371/journal.ppat.1005763[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVelu7rL&md5=0545e9836cf38a96b4ab000ca0a810bfOpen source drug discovery with the malaria box compound collection for neglected diseases and beyondVan Voorhis, Wesley C.; Adams, John H.; Adelfio, Roberto; Ahyong, Vida; Akabas, Myles H.; Alano, Pietro; Alday, Aintzane; Aleman Resto, Yesmalie; Alsibaee, Aishah; Alzualde, Ainhoa; Andrews, Katherine T.; Avery, Simon V.; Avery, Vicky M.; Ayong, Lawrence; Baker, Mark; Baker, Stephen; Ben Mamoun, Choukri; Bhatia, Sangeeta; Bickle, Quentin; Bounaadja, Lotfi; Bowling, Tana; Bosch, Jurgen; Boucher, Lauren E.; Boyom, Fabrice F.; Brea, Jose; Brennan, Marian; Burton, Audrey; Caffrey, Conor R.; Camarda, Grazia; Carrasquilla, Manuela; Carter, Dee; Cassera, Maria Belen; Cheng, Ken Chih-Chien; Chindaudomsate, Worathad; Chubb, Anthony; Colon, Beatrice L.; Colon-Lopez, Daisy D.; Corbett, Yolanda; Crowther, Gregory J.; Cowan, Noemi; D'Alessandro, Sarah; Dang, Na Le; Delves, Michael; De Risi, Joseph L.; Du, Alan Y.; Duffy, Sandra; El-Sayed, Shimaa Abd El-Salam; Ferdig, Michael T.; Fernandez Robledo, Jose A.; Fidock, David A.; Florent, Isabelle; Fokou, Patrick V. T.; Galstian, Ani; Gamo, Francisco Javier; Gokool, Suzanne; Gold, Ben; Golub, Todd; Goldgof, Gregory M.; Guha, Rajarshi; Guiguemde, W. Armand; Gural, Nil; Guy, R. Kiplin; Hansen, Michael A. E.; Hanson, Kirsten K.; Hemphill, Andrew; Hooft van Huijsduijnen, Rob; Horii, Takaaki; Horrocks, Paul; Hughes, Tyler B.; Huston, Christopher; Igarashi, Ikuo; Ingram-Sieber, Katrin; Itoe, Maurice A.; Jadhav, Ajit; Jensen, Amornrat Naranuntarat; Jensen, Laran T.; Jiang, Rays H. Y.; Kaiser, Annette; Keiser, Jennifer; Ketas, Thomas; Kicka, Sebastien; Kim, Sunyoung; Kirk, Kiaran; Kumar, Vidya P.; Kyle, Dennis E.; Lafuente, Maria Jose; Landfear, Scott; Lee, Nathan; Lee, Sukjun; Lehane, Adele M.; Li, Fengwu; Little, David; Liu, Liqiong; Llinas, Manuel; Loza, Maria I.; Lubar, Aristea; Lucantoni, Leonardo; Lucet, Isabelle; Maes, Louis; Mancama, Dalu; Mansour, Nuha R.; March, Sandra; McGowan, Sheena; Vera, Iset Medina; Meister, Stephan; Mercer, Luke; Mestres, Jordi; Mfopa, Alvine N.; Misra, Raj N.; Moon, Seunghyun; Moore, John P.; Morais Rodrigues da Costa, Francielly; Muller, Joachim; Muriana, Arantza; Hewitt, Stephen Nakazawa; Nare, Bakela; Nathan, Carl; Narraidoo, Nathalie; Nawaratna, Sujeevi; Ojo, Kayode K.; Ortiz, Diana; Panic, Gordana; Papadatos, George; Parapini, Silvia; Patra, Kailash; Pham, Ngoc; Prats, Sarah; Plouffe, David M.; Poulsen, Sally-Ann; Pradhan, Anupam; Quevedo, Celia; Quinn, Ronald J.; Rice, Christopher A.; Rizk, Mohamed Abdo; Ruecker, Andrea; St. Onge, Robert; Ferreira, Rafaela Salgado; Samra, Jasmeet; Robinett, Natalie G.; Schlecht, Ulrich; Schmitt, Marjorie; Villela, Filipe Silva; Silvestrini, Francesco; Sinden, Robert; Smith, Dennis A.; Soldati, Thierry; Spitzmuller, Andreas; Stamm, Serge Maximilian; Sullivan, David J.; Sullivan, William; Suresh, Sundari; Suzuki, Brian M.; Suzuki, Yo; Swamidass, S. Joshua; Taramelli, Donatella; Tchokouaha, Lauve R. Y.; Theron, Anjo; Thomas, David; Tonissen, Kathryn F.; Townson, Simon; Tripathi, Abhai K.; Trofimov, Valentin; Udenze, Kenneth O.; Ullah, Imran; Vallieres, Cindy; Vigil, Edgar; Vinetz, Joseph M.; Vinh, Phat Voong; Vu, Hoan; Watanabe, Nao-aki; Weatherby, Kate; White, Pamela M.; Wilks, Andrew F.; Winzeler, Elizabeth A.; Wojcik, Edward; Wree, Melanie; Wu, Wesley; Yokoyama, Naoaki; Zollo, Paul H. A.; Abla, Nada; Blasco, Benjamin; Burrows, Jeremy; Laleu, Benoit; Leroy, Didier; Spangenberg, Thomas; Wells, Timothy; Willis, Paul A.PLoS Pathogens (2016), 12 (7), e1005763/1-e1005763/23CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biol. is present in universities, whereas the focus of medicinal chem. is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could esp. be bridged through a scale-up of open sharing of phys. compds., which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compds. representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-anal. of the combined dataset. The combined biochem. and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compds. active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addn., many compds. demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicol., pharmacokinetic and metabolic properties were collected on all the compds., assisting in the selection of the most promising candidates for murine proof-of-concept expts. and medicinal chem. programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biol. assays involving human pathogens into drug discovery starting points, by providing open access to new families of mols., and emphasize how a small addnl. investment made to help acquire and distribute compds., and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chem. efforts.
- 13Goodnow, R. A., Jr.; Dumelin, C. E.; Keefe, A. D. DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nat. Rev. Drug Discovery 2017, 16, 131– 147, DOI: 10.1038/nrd.2016.213[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVKkurjM&md5=7ca97b01d75e600378799baf77665c07DNA-encoded chemistry: enabling the deeper sampling of chemical spaceGoodnow, Robert A. Jr; Dumelin, Christoph E.; Keefe, Anthony D.Nature Reviews Drug Discovery (2017), 16 (2), 131-147CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. DNA-encoded chem. library technologies are increasingly being adopted in drug discovery for hit and lead generation. DNA-encoded chem. enables the exploration of chem. spaces four to five orders of magnitude more deeply than is achievable by traditional high-throughput screening methods. Operation of this technol. requires developing a range of capabilities including aq. synthetic chem., building block acquisition, oligonucleotide conjugation, large-scale mol. biol. transformations, selection methodologies, PCR, sequencing, sequence data anal. and the anal. of large chem. spaces. This Review provides an overview of the development and applications of DNA-encoded chem., highlighting the challenges and future directions for the use of this technol.
- 14Yuthavong, Y.; Tarnchompoo, B.; Vilaivan, T.; Chitnumsub, P.; Kamchonwongpaisan, S.; Charman, S. A.; McLennan, D. N.; White, K. L.; Vivas, L.; Bongard, E.; Thongphanchang, C.; Taweechai, S.; Vanichtanankul, J.; Rattanajak, R.; Arwon, U.; Fantauzzi, P.; Yuvaniyama, J.; Charman, W. N.; Matthews, D. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 16823– 16828, DOI: 10.1073/pnas.1204556109[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1WksL7M&md5=7ef675391becc919f718de74fa61550bMalarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised targetYuthavong, Yongyuth; Tarnchompoo, Bongkoch; Vilaivan, Tirayut; Chitnumsub, Penchit; Kamchonwongpaisan, Sumalee; Charman, Susan A.; McLennan, Danielle N.; White, Karen L.; Vivas, Livia; Bongard, Emily; Thongphanchang, Chawanee; Taweechai, Supannee; Vanichtanankul, Jarunee; Rattanajak, Roonglawan; Arwon, Uthai; Fantauzzi, Pascal; Yuvaniyama, Jirundon; Charman, William N.; Matthews, DavidProceedings of the National Academy of Sciences of the United States of America (2012), 109 (42), 16823-16828, S16823/1-S16823/9CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clin. efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclin. development of a selective, highly efficacious, and orally available antimalarial drug candidate (P218) that potently inhibits both wild-type and clin. relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of PfDHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant PfDHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development.
- 15Yang, T.; Ottilie, S.; Istvan, E. S.; Godinez-Macias, K. P.; Lukens, A. K.; Baragaña, B.; Campo, B.; Walpole, C.; Niles, J. C.; Chibale, K.; Dechering, K. J.; Llinás, M.; Lee, M. C. S.; Kato, N.; Wyllie, S.; McNamara, C. W.; Gamo, F. J.; Burrows, J.; Fidock, D. A.; Goldberg, D. E.; Gilbert, I. H.; Wirth, D. F.; Winzeler, E. A. MalDA, Accelerating Malaria Drug Discovery. Trends Parasitol. 2021, 37, 493– 507, DOI: 10.1016/j.pt.2021.01.009[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXosVOmur4%253D&md5=7e9ca6289fc74201d9bb49cf32d4aca0Malaria Drug Accelerator, Accelerating Malaria Drug DiscoveryYang, Tuo; Ottilie, Sabine; Istvan, Eva S.; Godinez-Macias, Karla P.; Lukens, Amanda K.; Baragana, Beatriz; Campo, Brice; Walpole, Chris; Niles, Jacquin C.; Chibale, Kelly; Dechering, Koen J.; Llinas, Manuel; Lee, Marcus C. S.; Kato, Nobutaka; Wyllie, Susan; McNamara, Case W.; Gamo, Francisco Javier; Burrows, Jeremy; Fidock, David A.; Goldberg, Daniel E.; Gilbert, Ian H.; Wirth, Dyann F.; Winzeler, Elizabeth A.Trends in Parasitology (2021), 37 (6), 493-507CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)A review. The Malaria Drug Accelerator (MalDA) is a consortium of 15 leading scientific labs. The aim of MalDA is to improve and accelerate the early antimalarial drug discovery process by identifying new, essential, druggable targets. In addn., it seeks to produce early lead inhibitors that may be advanced into drug candidates suitable for preclin. development and subsequent clin. testing in humans. By sharing resources, including expertise, knowledge, materials, and reagents, the consortium strives to eliminate the structural barriers often encountered in the drug discovery process. Here we discuss the mission of the consortium and its scientific achievements, including the identification of new chem. and biol. validated targets, as well as future scientific directions.
- 16Carolino, K.; Winzeler, E. A. The antimalarial resistome - finding new drug targets and their modes of action. Curr. Opin. Microbiol. 2020, 57, 49– 55, DOI: 10.1016/j.mib.2020.06.004[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlaju77I&md5=66b977eedbf79997dbf956b50101c13eThe antimalarial resistome - finding new drug targets and their modes of actionCarolino, Krypton; Winzeler, Elizabeth A.Current Opinion in Microbiology (2020), 57 (), 49-55CODEN: COMIF7; ISSN:1369-5274. (Elsevier Ltd.)A review. To this day, malaria remains a global burden, affecting millions of people, esp. those in sub-Saharan Africa and Asia. The rise of drug resistance to current antimalarial treatments, including artemisinin-based combination therapies, has made discovering new small mol. compds. with novel modes of action an urgent matter. The concerted effort to construct enormous compd. libraries and develop high-throughput phenotypic screening assays to find compds. effective at specifically clearing malaria-causing Plasmodium parasites at any stage of the life cycle has provided many antimalarial prospects, but does not indicate their target or mode of action. Here, we review recent advances in antimalarial drug discovery efforts, focusing on the following 'omics' approaches in mode of action studies: IVIEWGA, CETSA, metabolomic profiling.
- 17Luth, M. R.; Gupta, P.; Ottilie, S.; Winzeler, E. A. Using in Vitro Evolution and Whole Genome Analysis To Discover Next Generation Targets for Antimalarial Drug Discovery. ACS Infect. Dis. 2018, 4, 301– 314, DOI: 10.1021/acsinfecdis.7b00276[ACS Full Text], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivVahu70%253D&md5=3d46f38b82a7c3276832463c5dd29c2cUsing in Vitro Evolution and Whole Genome Analysis To Discover Next Generation Targets for Antimalarial Drug DiscoveryLuth, Madeline R.; Gupta, Purva; Ottilie, Sabine; Winzeler, Elizabeth A.ACS Infectious Diseases (2018), 4 (3), 301-314CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)A review. Although many new anti-infectives have been discovered and developed solely using phenotypic cellular screening and assay optimization, most researchers recognize that structure-guided drug design is more practical and less costly. In addn., a greater chem. space can be interrogated with structure-guided drug design. The practicality of structure-guided drug design has launched a search for the targets of compds. discovered in phenotypic screens. One method that has been used extensively in malaria parasites for target discovery and chem. validation is in vitro evolution and whole genome anal. (IVIEWGA). Here, small mols. from phenotypic screens with demonstrated antiparasitic activity are used in genome-based target discovery methods. In this Review, we discuss the newest, most promising druggable targets discovered or further validated by evolution-based methods, as well as some exceptions.
- 18Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.; Cohen, S. B.; Spencer, K. R.; Gonzalez-Paez, G. E.; Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H.-P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.; Fidock, D. A.; Winzeler, E. A.; Diagana, T. T. Spiroindolones, a potent compound class for the treatment of malaria. Science 2010, 329, 1175– 1180, DOI: 10.1126/science.1193225[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtV2hsr%252FJ&md5=239bc9babd5cb5f07e2be38741038e2cSpiroindolones, a Potent Compound Class for the Treatment of MalariaRottmann, Matthias; McNamara, Case; Yeung, Bryan K. S.; Lee, Marcus C. S.; Zou, Bin; Russell, Bruce; Seitz, Patrick; Plouffe, David M.; Dharia, Neekesh V.; Tan, Jocelyn; Cohen, Steven B.; Spencer, Kathryn R.; Gonzalez-Paez, Gonzalo E.; Lakshminarayana, Suresh B.; Goh, Anne; Suwanarusk, Rossarin; Jegla, Timothy; Schmitt, Esther K.; Beck, Hans-Peter; Brun, Reto; Nosten, Francois; Renia, Laurent; Dartois, Veronique; Keller, Thomas H.; Fidock, David A.; Winzeler, Elizabeth A.; Diagana, Thierry T.Science (Washington, DC, United States) (2010), 329 (5996), 1175-1180CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Recent reports of increased tolerance to artemisinin derivs.-the most recently adopted class of antimalarials-have prompted a need for new treatments. The spirotetrahydro-β-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clin. isolates at low nanomolar concn. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
- 19Baragana, B.; Hallyburton, I.; Lee, M. C. S.; Norcross, N. R.; Grimaldi, R.; Otto, T. D.; Proto, W. R.; Blagborough, A. M.; Meister, S.; Wirjanata, G.; Ruecker, A.; Upton, L. M.; Abraham, T. S.; Almeida, M. J.; Pradhan, A.; Porzelle, A.; Martinez, M. S.; Bolscher, J. M.; Woodland, A.; Luksch, T.; Norval, S.; Zuccotto, F.; Thomas, J.; Simeons, F.; Stojanovski, L.; Osuna-Cabello, M.; Brock, P. M.; Churcher, T. S.; Sala, K. A.; Zakutansky, S. E.; Jimenez-Diaz, M. B.; Sanz, L. M.; Riley, J.; Basak, R.; Campbell, M.; Avery, V. M.; Sauerwein, R. W.; Dechering, K. J.; Noviyanti, R.; Campo, B.; Frearson, J. A.; Angulo-Barturen, I.; Ferrer-Bazaga, S.; Gamo, F. J.; Wyatt, P. G.; Leroy, D.; Siegl, P.; Delves, M. J.; Kyle, D. E.; Wittlin, S.; Marfurt, J.; Price, R. N.; Sinden, R. E.; Winzeler, E. A.; Charman, S. A.; Bebrevska, L.; Gray, D. W.; Campbell, S.; Fairlamb, A. H.; Willis, P. A.; Rayner, J. C.; Fidock, D. A.; Read, K. D.; Gilbert, I. H. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature 2015, 522, 315– 320, DOI: 10.1038/nature14451[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFeiurzE&md5=bd5f1dd3c4389aa8a6f193df0aa068a1A novel multiple-stage antimalarial agent that inhibits protein synthesisBaragana, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martinez, Maria Santos; Bolscher, Judith M.; Woodland, Andrew; Luksch, Torsten; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jimenez-Diaz, Maria Belen; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W.; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Inigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth A.; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul A.; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.Nature (London, United Kingdom) (2015), 522 (7556), 315-320CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compd. with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clin. needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening program against blood-stage malaria parasites; its mol. target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
- 20Corpas-Lopez, V.; Moniz, S.; Thomas, M.; Wall, R. J.; Torrie, L. S.; Zander-Dinse, D.; Tinti, M.; Brand, S.; Stojanovski, L.; Manthri, S.; Hallyburton, I.; Zuccotto, F.; Wyatt, P. G.; De Rycker, M.; Horn, D.; Ferguson, M. A. J.; Clos, J.; Read, K. D.; Fairlamb, A. H.; Gilbert, I. H.; Wyllie, S. Pharmacological Validation of N-Myristoyltransferase as a Drug Target in Leishmania donovani. ACS Infect. Dis. 2019, 5, 111– 122, DOI: 10.1021/acsinfecdis.8b00226[ACS Full Text], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVCisb%252FI&md5=5901cad939de2eb6beab6d4454e21acbPharmacological Validation of N-Myristoyltransferase as a Drug Target in Leishmania donovaniCorpas-Lopez, Victoriano; Moniz, Sonia; Thomas, Michael; Wall, Richard J.; Torrie, Leah S.; Zander-Dinse, Dorothea; Tinti, Michele; Brand, Stephen; Stojanovski, Laste; Manthri, Sujatha; Hallyburton, Irene; Zuccotto, Fabio; Wyatt, Paul G.; De Rycker, Manu; Horn, David; Ferguson, Michael A. J.; Clos, Joachim; Read, Kevin D.; Fairlamb, Alan H.; Gilbert, Ian H.; Wyllie, SusanACS Infectious Diseases (2019), 5 (1), 111-122CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and L. infantum, is responsible for ∼30,000 deaths annually. Available treatments are inadequate, and there is a pressing need for new therapeutics. N-Myristoyltransferase (NMT) remains one of the few genetically validated drug targets in these parasites. Here, the authors sought to pharmacol. validate this enzyme in Leishmania. A focused set of 1600 pyrazolyl sulfonamide compds. was screened against L. major NMT in a robust high-throughput biochem. assay. Several potent inhibitors were identified with marginal selectivity over the human enzyme. There was little correlation between the enzyme potency of these inhibitors and their cellular activity against L. donovani axenic amastigotes, and this discrepancy could be due to poor cellular uptake due to the basicity of these compds. Thus, a series of analogs were synthesized with less basic centers. Although most of these compds. continued to suffer from relatively poor antileishmanial activity, the authors' most potent inhibitor of LmNMT (DDD100097, Ki of 0.34 nM) showed modest activity against L. donovani intracellular amastigotes (EC50 of 2.4 μM) and maintained a modest therapeutic window over the human enzyme. Two unbiased approaches, namely, screening against the authors' cosmid-based overexpression library and thermal proteome profiling (TPP), confirm that DDD100097 (compd. 2) acts on-target within parasites. Oral dosing with compd. 2 resulted in a 52% redn. in parasite burden in the authors' mouse model of VL. Thus, NMT is now a pharmacol. validated target in Leishmania. The challenge in finding drug candidates remains to identify alternative strategies to address the drop-off in activity between enzyme inhibition and in vitro activity while maintaining sufficient selectivity over the human enzyme, both issues that continue to plague studies in this area.
- 21Hoepfner, D.; McNamara, C. W.; Lim, C. S.; Studer, C.; Riedl, R.; Aust, T.; McCormack, S. L.; Plouffe, D. M.; Meister, S.; Schuierer, S.; Plikat, U.; Hartmann, N.; Staedtler, F.; Cotesta, S.; Schmitt, E. K.; Petersen, F.; Supek, F.; Glynne, R. J.; Tallarico, J. A.; Porter, J. A.; Fishman, M. C.; Bodenreider, C.; Diagana, T. T.; Movva, N. R.; Winzeler, E. A. Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin. Cell Host Microbe 2012, 11, 654– 663, DOI: 10.1016/j.chom.2012.04.015[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XosFChtbk%253D&md5=ed482a3e7abcbf027f4223d45bdeebd8Selective and specific inhibition of the Plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporinHoepfner, Dominic; McNamara, Case W.; Lim, Chek Shik; Studer, Christian; Riedl, Ralph; Aust, Thomas; McCormack, Susan L.; Plouffe, David M.; Meister, Stephan; Schuierer, Sven; Plikat, Uwe; Hartmann, Nicole; Staedtler, Frank; Cotesta, Simona; Schmitt, Esther K.; Petersen, Frank; Supek, Frantisek; Glynne, Richard J.; Tallarico, John A.; Porter, Jeffrey A.; Fishman, Mark C.; Bodenreider, Christophe; Diagana, Thierry T.; Movva, N. Rao; Winzeler, Elizabeth A.Cell Host & Microbe (2012), 11 (6), 654-663CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)With renewed calls for malaria eradication, next-generation antimalarials need be active against drug-resistant parasites and efficacious against both liver- and blood-stage infections. The authors screened a natural product library to identify inhibitors of Plasmodium falciparum blood and liver stage proliferation. Cladosporin, a fungal secondary metabolite whose target and mechanism of action are not known for any species, was identified as having potent, nanomolar, antiparasitic activity against both blood and liver stages. Using postgenomic methods, including a yeast deletion strains collection, the authors show that cladosporin specifically inhibits protein synthesis by directly targeting P. falciparum cytosolic lysyl-tRNA synthetase. Further, cladosporin is >100-fold more potent against parasite lysyl-tRNA synthetase relative to the human enzyme, which is conferred by the identity of two amino acids within the enzyme active site. The data indicate that lysyl-tRNA synthetase is an attractive, druggable, antimalarial target that can be selectively inhibited.
- 22Kato, N.; Comer, E.; Sakata-Kato, T.; Sharma, A.; Sharma, M.; Maetani, M.; Bastien, J.; Brancucci, N. M.; Bittker, J. A.; Corey, V.; Clarke, D.; Derbyshire, E. R.; Dornan, G. L.; Duffy, S.; Eckley, S.; Itoe, M. A.; Koolen, K. M. J.; Lewis, T. A.; Lui, P. S.; Lukens, A. K.; Lund, E.; March, S.; Meibalan, E.; Meier, B. C.; McPhail, J. A.; Mitasev, B.; Moss, E. L.; Sayes, M.; Van Gessel, Y.; Wawer, M. J.; Yoshinaga, T.; Zeeman, A.-M.; Avery, V. M.; Bhatia, S. N.; Burke, J. E.; Catteruccia, F.; Clardy, J. C.; Clemons, P. A.; Dechering, K. J.; Duvall, J. R.; Foley, M. A.; Gusovsky, F.; Kocken, C. H. M.; Marti, M.; Morningstar, M. L.; Munoz, B.; Neafsey, D. E.; Sharma, A.; Winzeler, E. A.; Wirth, D. F.; Scherer, C. A.; Schreiber, S. L. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature 2016, 538, 344– 349, DOI: 10.1038/nature19804[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslWhsLrI&md5=68e6e2018f2d49278d255ee02bfc8d16Diversity-oriented synthesis yields novel multistage antimalarial inhibitorsKato, Nobutaka; Comer, Eamon; Sakata-Kato, Tomoyo; Sharma, Arvind; Sharma, Manmohan; Maetani, Micah; Bastien, Jessica; Brancucci, Nicolas M.; Bittker, Joshua A.; Corey, Victoria; Clarke, David; Derbyshire, Emily R.; Dornan, Gillian L.; Duffy, Sandra; Eckley, Sean; Itoe, Maurice A.; Koolen, Karin M. J.; Lewis, Timothy A.; Lui, Ping S.; Lukens, Amanda K.; Lund, Emily; March, Sandra; Meibalan, Elamaran; Meier, Bennett C.; McPhail, Jacob A.; Mitasev, Branko; Moss, Eli L.; Sayes, Morgane; Van Gessel, Yvonne; Wawer, Mathias J.; Yoshinaga, Takashi; Zeeman, Anne-Marie; Avery, Vicky M.; Bhatia, Sangeeta N.; Burke, John E.; Catteruccia, Flaminia; Clardy, Jon C.; Clemons, Paul A.; Dechering, Koen J.; Duvall, Jeremy R.; Foley, Michael A.; Gusovsky, Fabian; Kocken, Clemens H. M.; Marti, Matthias; Morningstar, Marshall L.; Munoz, Benito; Neafsey, Daniel E.; Sharma, Amit; Winzeler, Elizabeth A.; Wirth, Dyann F.; Scherer, Christina A.; Schreiber, Stuart L.Nature (London, United Kingdom) (2016), 538 (7625), 344-349CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compds. Here the authors investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compds. that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. The authors report the identification of such compds. with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These mols. are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. The authors' findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.
- 23Herman, J. D.; Pepper, L. R.; Cortese, J. F.; Estiu, G.; Galinsky, K.; Zuzarte-Luis, V.; Derbyshire, E. R.; Ribacke, U.; Lukens, A. K.; Santos, S. A.; Patel, V.; Clish, C. B.; Sullivan, W. J., Jr.; Zhou, H.; Bopp, S. E.; Schimmel, P.; Lindquist, S.; Clardy, J.; Mota, M. M.; Keller, T. L.; Whitman, M.; Wiest, O.; Wirth, D. F.; Mazitschek, R. The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Sci. Transl. Med. 2015, 7, 288ra77, DOI: 10.1126/scitranslmed.aaa3575
- 24Gilbert, I. H. Drug discovery for neglected diseases: Molecular target-based and phenotypic approaches. J. Med. Chem. 2013, 56, 7719– 7726, DOI: 10.1021/jm400362b[ACS Full Text], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVWkur%252FF&md5=dcc54f2ed7987c3089bbe4944b747420Drug Discovery for Neglected Diseases: Molecular Target-Based and Phenotypic ApproachesGilbert, Ian H.Journal of Medicinal Chemistry (2013), 56 (20), 7719-7726CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Drug discovery for neglected tropical diseases is carried out using both target-based and phenotypic approaches. In this paper, target-based approaches are discussed, with a particular focus on human African trypanosomiasis. Target-based drug discovery can be successful, but careful selection of targets is required. There are still very few fully validated drug targets in neglected diseases, and there is a high attrition rate in target-based drug discovery for these diseases. Phenotypic screening is a powerful method in both neglected and non-neglected diseases and has been very successfully used. Identification of mol. targets from phenotypic approaches can be a way to identify potential new drug targets.
- 25Frearson, J. A.; Wyatt, P. G.; Gilbert, I. H.; Fairlamb, A. H. Target assessment for antiparasitic drug discovery. Trends Parasitol. 2007, 23, 589– 595, DOI: 10.1016/j.pt.2007.08.019[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVSktrzJ&md5=40edb0aa482e5b6155dc653397c1c45dTarget assessment for antiparasitic drug discoveryFrearson, Julie A.; Wyatt, Paul G.; Gilbert, Ian H.; Fairlamb, Alan H.Trends in Parasitology (2007), 23 (12), 589-595CODEN: TPRACT; ISSN:1471-4922. (Elsevier B.V.)A review. Drug discovery is a high-risk, expensive and lengthy process taking at least 12 years and costing upwards of US$500 million per drug to reach the clinic. For neglected diseases, the drug discovery process is driven by medical need and guided by pre-defined target product profiles. Assessment and prioritization of the most promising targets for entry into screening programs is crucial for maximizing the chances of success. Here, we describe criteria used in our drug discovery unit for target assessment and introduce the 'traffic-light' system as a prioritization and management tool. We hope this brief review will stimulate basic scientists to acquire addnl. information necessary for drug discovery.
- 26Gilbert, I. H. Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matter. Parasitology 2014, 141, 28– 36, DOI: 10.1017/S0031182013001017[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sfotlSqtQ%253D%253D&md5=0a069387de0bdc08edc20951a27452d9Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matterGilbert Ian HParasitology (2014), 141 (1), 28-36 ISSN:.Target-based approaches for human African trypanosomiasis (HAT) and related parasites can be a valuable route for drug discovery for these diseases. However, care needs to be taken in selection of both the actual drug target and the chemical matter that is developed. In this article, potential criteria to aid target selection are described. Then the physiochemical properties of typical oral drugs are discussed and compared to those of known anti-parasitics.
- 27Wyatt, P. G.; Gilbert, I. H.; Read, K. D.; Fairlamb, A. H. Target Validation: Linking Target and Chemical Properties to Desired Product Profile. Curr. Top. Med. Chem. 2011, 11, 1275– 1283, DOI: 10.2174/156802611795429185[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnt1Cnsb4%253D&md5=ad865a1eb11fc8f175be5aba2866028dTarget validation: linking target and chemical properties to desired product profileWyatt, Paul G.; Gilbert, Ian H.; Read, Kevin D.; Fairlamb, Alan H.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2011), 11 (10), 1275-1283CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. The discovery of drugs is a lengthy, high-risk and expensive business taking at least 12 years and is estd. to cost upwards of US$800 million for each drug to be successfully approved for clin. use. Much of this cost is driven by the late phase clin. trials and therefore the ability to terminate early those projects destined to fail is paramount to prevent unwanted costs and wasted effort. Although neglected diseases drug discovery is driven more by unmet medical need rather than financial considerations, the need to minimize wasted money and resources is even more vital in this under-funded area. To ensure any drug discovery project is addressing the requirements of the patients and health care providers and delivering a benefit over existing therapies, the ideal attributes of a novel drug needs to be pre-defined by a set of criteria called a target product profile. Using a target product profile the drug discovery process, clin. study design, and compd. characteristics can be defined all the way back through to the suitability or druggability of the intended biochem. target. Assessment and prioritization of the most promising targets for entry into screening programs is crucial for maximizing chances of success.
- 28Chaparro, M. J.; Calderón, F.; Castañeda, P.; Fernández-Alvaro, E.; Gabarró, R.; Gamo, F. J.; Gómez-Lorenzo, M. G.; Martín, J.; Fernández, E. Efforts Aimed To Reduce Attrition in Antimalarial Drug Discovery: A Systematic Evaluation of the Current Antimalarial Targets Portfolio. ACS Infect. Dis. 2018, 4, 568– 576, DOI: 10.1021/acsinfecdis.7b00211[ACS Full Text], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmt1Wktg%253D%253D&md5=1ddb89e0ebe4b40b54d1ecc097ad40c5Efforts Aimed To Reduce Attrition in Antimalarial Drug Discovery: A Systematic Evaluation of the Current Antimalarial Targets PortfolioChaparro, Maria Jesus; Calderon, Felix; Castaneda, Pablo; Fernandez-Alvaro, Elena; Gabarro, Raquel; Gamo, Francisco Javier; Gomez-Lorenzo, Maria G.; Martin, Julio; Fernandez, EstherACS Infectious Diseases (2018), 4 (4), 568-576CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and more than 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (artemisinin combination therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes of action, able to relieve symptoms as fast as the artemisinins and/or block malaria transmission. During the past few years, the antimalarial community has focused their efforts on phenotypic screening as a pragmatic approach to identify new hits. Optimization efforts on several chem. series have been successful, and clin. candidates have been identified. In addn., recent advances in genetics and proteomics have led to the target deconvolution of phenotypic clin. candidates. New mechanisms of action will also be crit. to overcome resistance and reduce attrition. Therefore, a complementary strategy focused on identifying well-validated targets to start hit identification programs is essential to reinforce the clin. pipeline. Leveraging published data, the authors have assessed the status quo of the current antimalarial target portfolio with a focus on the blood stage clin. disease. From an extensive list of reported Plasmodium targets, the authors have defined triage criteria. These criteria consider genetic, pharmacol., and chem. validation, as well as tractability/doability, and safety implications. These criteria have provided a quant. score that has led the authors to prioritize those targets with the highest probability to deliver successful and differentiated new drugs.
- 29Gashaw, I.; Ellinghaus, P.; Sommer, A.; Asadullah, K. What makes a good drug target?. Drug Discovery Today 2011, 16, 1037– 1043, DOI: 10.1016/j.drudis.2011.09.007[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFCqs73K&md5=e95c90b75d4797df0230253a3c34d7edWhat makes a good drug target?Gashaw, Isabella; Ellinghaus, Peter; Sommer, Anette; Asadullah, KhusruDrug Discovery Today (2011), 16 (23/24), 1037-1043CODEN: DDTOFS; ISSN:1359-6446. (Elsevier B.V.)A review. Novel therapeutics in areas with a high unmet medical need are based on innovative drug targets. Although biologicals' have enlarged the space of druggable mols., the no. of appropriate drug targets is still limited. Discovering and assessing the potential therapeutic benefit of a drug target is based not only on exptl., mechanistic and pharmacol. studies but also on a theor. mol. druggability assessment, an early evaluation of potential side effects and considerations regarding opportunities for commercialization. This article defines key properties of a good drug target from the perspective of a pharmaceutical company.
- 30Nasamu, A. S.; Falla, A.; Pasaje, C. F. A.; Wall, B. A.; Wagner, J. C.; Ganesan, S. M.; Goldfless, S. J.; Niles, J. C. An integrated platform for genome engineering and gene expression perturbation in Plasmodium falciparum. Sci. Rep. 2021, 11, 342, DOI: 10.1038/s41598-020-77644-4[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtF2qt7k%253D&md5=347bfa9260e2fe7648f2c985ce5d8dcaAn integrated platform for genome engineering and gene expression perturbation in Plasmodium falciparumNasamu, Armiyaw S.; Falla, Alejandra; Pasaje, Charisse Flerida A.; Wall, Bridget A.; Wagner, Jeffrey C.; Ganesan, Suresh M.; Goldfless, Stephen J.; Niles, Jacquin C.Scientific Reports (2021), 11 (1), 342CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)Establishing robust genome engineering methods in the malarial parasite, Plasmodium falciparum, has the potential to substantially improve the efficiency with which we gain understanding of this pathogen's biol. to propel treatment and elimination efforts. Methods for manipulating gene expression and engineering the P. falciparum genome have been validated. However, a significant barrier to fully leveraging these advances is the difficulty assocd. with assembling the extremely high AT content DNA constructs required for modifying the P. falciparum genome. These are frequently unstable in commonly-used circular plasmids. We address this bottleneck by devising a DNA assembly framework leveraging the improved reliability with which large AT-rich regions can be efficiently manipulated in linear plasmids. This framework integrates several key functional genetics outcomes via CRISPR/Cas9 and other methods from a common, validated framework. Overall, this mol. toolkit enables P. falciparum genetics broadly and facilitates deeper interrogation of parasite genes involved in diverse biol. processes.
- 31Ganesan, S. M.; Falla, A.; Goldfless, S. J.; Nasamu, A. S.; Niles, J. C. Synthetic RNA-protein modules integrated with native translation mechanisms to control gene expression in malaria parasites. Nat. Commun. 2016, 7, 10727, DOI: 10.1038/ncomms10727[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsVaruro%253D&md5=67a9f9b62eaa8fc7c802a10c0ce0b13cSynthetic RNA-protein modules integrated with native translation mechanisms to control gene expression in malaria parasitesGanesan, Suresh M.; Falla, Alejandra; Goldfless, Stephen J.; Nasamu, Armiyaw S.; Niles, Jacquin C.Nature Communications (2016), 7 (), 10727CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)Synthetic posttranscriptional regulation of gene expression is important for understanding fundamental biol. and programming new cellular processes in synthetic biol. Previous strategies for regulating translation in eukaryotes have focused on disrupting individual steps in translation, including initiation and mRNA cleavage. In emphasizing modularity and cross-organism functionality, these systems are designed to operate orthogonally to native control mechanisms. Here we introduce a broadly applicable strategy for robustly controlling protein translation by integrating synthetic translational control via a small-mol.-regulated RNA-protein module with native mechanisms that simultaneously regulate multiple facets of cellular RNA fate. We demonstrate that this strategy reduces 'leakiness' to improve overall expression dynamic range, and can be implemented without sacrificing modularity and cross-organism functionality. We illustrate this in Saccharomyces cerevisiae and the non-model human malarial parasite, Plasmodium falciparum. Given the limited functional genetics toolkit available for P. falciparum, we establish the utility of this strategy for defining essential genes.
- 32Pisa, R.; Kapoor, T. M. Chemical strategies to overcome resistance against targeted anticancer therapeutics. Nat. Chem. Biol. 2020, 16, 817– 825, DOI: 10.1038/s41589-020-0596-8[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVagsr%252FI&md5=e660ceac1742d78cae3670710ad5731fChemical strategies to overcome resistance against targeted anticancer therapeuticsPisa, Rudolf; Kapoor, Tarun M.Nature Chemical Biology (2020), 16 (8), 817-825CODEN: NCBABT; ISSN:1552-4450. (Nature Research)Abstr.: Emergence of resistance is a major factor limiting the efficacy of molecularly targeted anticancer drugs. Understanding the specific mutations, or other genetic or cellular changes, that confer drug resistance can help in the development of therapeutic strategies with improved efficacies. Here, we outline recent progress in understanding chemotype-specific mechanisms of resistance and present chem. strategies, such as designing drugs with distinct binding modes or using proteolysis targeting chimeras, to overcome resistance. We also discuss how targeting multiple binding sites with bifunctional inhibitors or identifying collateral sensitivity profiles can be exploited to limit the emergence of resistance. Finally, we highlight how incorporating analyses of resistance early in drug development can help with the design and evaluation of therapeutics that can have long-term benefits for patients. [graphic not available: see fulltext].
- 33Zhang, M.; Wang, C.; Otto, T. D.; Oberstaller, J.; Liao, X.; Adapa, S. R.; Udenze, K.; Bronner, I. F.; Casandra, D.; Mayho, M.; Brown, J.; Li, S.; Swanson, J.; Rayner, J. C.; Jiang, R. H. Y.; Adams, J. H. Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis. Science 2018, 360, eaap7847, DOI: 10.1126/science.aap7847
- 34Bushell, E.; Gomes, A. R.; Sanderson, T.; Anar, B.; Girling, G.; Herd, C.; Metcalf, T.; Modrzynska, K.; Schwach, F.; Martin, R. E.; Mather, M. W.; McFadden, G. I.; Parts, L.; Rutledge, G. G.; Vaidya, A. B.; Wengelnik, K.; Rayner, J. C.; Billker, O. Functional profiling of a Plasmodium genome reveals an abundance of essential genes. Cell 2017, 170, 260– 272, DOI: 10.1016/j.cell.2017.06.030[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFygtbzN&md5=c7745367d9db0a8112aa59f7fb9ebe70Functional profiling of a plasmodium genome reveals an abundance of essential genesBushell, Ellen; Gomes, Ana Rita; Sanderson, Theo; Anar, Burcu; Girling, Gareth; Herd, Colin; Metcalf, Tom; Modrzynska, Katarzyna; Schwach, Frank; Martin, Rowena E.; Mather, Michael W.; McFadden, Geoffrey I.; Parts, Leopold; Rutledge, Gavin G.; Vaidya, Akhil B.; Wengelnik, Kai; Rayner, Julian C.; Billker, OliverCell (Cambridge, MA, United States) (2017), 170 (2), 260-272.e8CODEN: CELLB5; ISSN:0092-8674. (Cell Press)The genomes of malaria parasites contain many genes of unknown function. To assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2578 barcoded Plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. At a single stage of its complex life cycle, P. berghei requires two-thirds of genes for optimal growth, the highest proportion reported from any organism and a probable consequence of functional optimization necessitated by genomic redns. during the evolution of parasitism. In contrast, extreme functional redundancy has evolved among expanded gene families operating at the parasite-host interface. The level of genetic redundancy in a single-celled organism may thus reflect the degree of environmental variation it experiences. In the case of Plasmodium parasites, this helps rationalize both the relative successes of drugs and the greater difficulty of making an effective vaccine.
- 35Ding, X. C.; Ubben, D.; Wells, T. N. A framework for assessing the risk of resistance for anti-malarials in development. Malar. J. 2012, 11, 292, DOI: 10.1186/1475-2875-11-292[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bgsVagtQ%253D%253D&md5=69e59ccb7d2a87dad485437582ae09d0A framework for assessing the risk of resistance for anti-malarials in developmentDing Xavier C; Ubben David; Wells Timothy N CMalaria journal (2012), 11 (), 292 ISSN:.Resistance is a constant challenge for anti-infective drug development. Since they kill sensitive organisms, anti-infective agents are bound to exert an evolutionary pressure toward the emergence and spread of resistance mechanisms, if such resistance can arise by stochastic mutation events. New classes of medicines under development must be designed or selected to stay ahead in this vicious circle of resistance control. This involves both circumventing existing resistance mechanisms and selecting molecules which are resilient against the development and spread of resistance. Cell-based screening methods have led to a renaissance of new classes of anti-malarial medicines, offering us the potential to select and modify molecules based on their resistance potential. To that end, a standardized in vitro methodology to assess quantitatively these characteristics in Plasmodium falciparum during the early phases of the drug development process has been developed and is presented here. It allows the identification of anti-malarial compounds with overt resistance risks and the prioritization of the most robust ones. The integration of this strategy in later stages of development, registration, and deployment is also discussed.
- 36Duffey, M.; Blasco, B.; Burrows, J. N.; Wells, T. N. C.; Fidock, D.; Leroy, D. Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials. Trends Parasitol. 2021, 37, 709– 721, DOI: 10.1016/j.pt.2021.04.006[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXht1Git77J&md5=e31d7cac81ad93ef9e9709bac2741202Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarialsDuffey, Maelle; Blasco, Benjamin; Burrows, Jeremy N.; Wells, Timothy N. C.; Fidock, David A.; Leroy, DidierTrends in Parasitology (2021), 37 (8), 709-721CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)A review. Strategies to counteract or prevent emerging drug resistance are crucial for the design of next-generation antimalarials. In the past, resistant parasites were generally identified following treatment failures in patients, and compds. would have to be abandoned late in development. An early understanding of how candidate therapeutics lose efficacy as parasites evolve resistance is important to facilitate drug design and improve resistance detection and monitoring up to the postregistration phase. We describe a new strategy to assess resistance to antimalarial compds. as early as possible in preclin. development by leveraging tools to define the Plasmodium falciparum resistome, predict potential resistance risks of clin. failure for candidate therapeutics, and inform decisions to guide antimalarial drug development.
- 37Ahouidi, A.; Ali, M.; Almagro-Garcia, J.; Amambua-Ngwa, A.; Amaratunga, C.; Amato, R.; Amenga-Etego, L.; Andagalu, B.; Anderson, T.; Andrianaranjaka, V.; Apinjoh, T.; Ariani, C.; Ashley, E.; Auburn, S.; Awandare, G.; Ba, H.; Baraka, V.; Barry, A.; Bejon, P.; Bertin, G.; Boni, M.; Borrmann, S.; Bousema, T.; Branch, O.; Bull, P.; Busby, G.; Chookajorn, T.; Chotivanich, K.; Claessens, A.; Conway, D.; Craig, A.; D’Alessandro, U.; Dama, S.; Day, N.; Denis, B.; Diakite, M.; DjimdÈ, A.; Dolecek, C.; Dondorp, A.; Drakeley, C.; Drury, E.; Duffy, P.; Echeverry, D.; Egwang, T.; Erko, B.; Fairhurst, R.; Faiz, A.; Fanello, C.; Fukuda, M.; Gamboa, D.; Ghansah, A.; Golassa, L.; Goncalves, S.; Hamilton, W.; Harrison, G.; Hart, L.; Henrichs, C.; Hien, T.; Hill, C.; Hodgson, A.; Hubbart, C.; Imwong, M.; Ishengoma, D.; Jackson, S.; Jacob, C.; Jeffery, B.; Jeffreys, A.; Johnson, K.; Jyothi, D.; Kamaliddin, C.; Kamau, E.; Kekre, M.; Kluczynski, K.; Kochakarn, T.; KonatÈ, A.; Kwiatkowski, D.; Kyaw, M.; Lim, P.; Lon, C.; Loua, K.; MaÔga-AscofarÈ, O.; Malangone, C.; Manske, M.; Marfurt, J.; Marsh, K.; Mayxay, M.; Miles, A.; Miotto, O.; Mobegi, V.; Mokuolu, O.; Montgomery, J.; Mueller, I.; Newton, P.; Nguyen, T.; Nguyen, T.; Noedl, H.; Nosten, F.; Noviyanti, R.; Nzila, A.; Ochola-Oyier, L.; Ocholla, H.; Oduro, A.; Omedo, I.; Onyamboko, M.; Ouedraogo, J.; Oyebola, K.; Pearson, R.; Peshu, N.; Phyo, A.; Plowe, C.; Price, R.; Pukrittayakamee, S.; Randrianarivelojosia, M.; Rayner, J.; Ringwald, P.; Rockett, K.; Rowlands, K.; Ruiz, L.; Saunders, D.; Shayo, A.; Siba, P.; Simpson, V.; Stalker, J.; Su, X.; Sutherland, C.; Takala-Harrison, S.; Tavul, L.; Thathy, V.; Tshefu, A.; Verra, F.; Vinetz, J.; Wellems, T.; Wendler, J.; White, N.; Wright, I.; Yavo, W.; Ye, H. An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples. Wellcome Open Res. 2021, 6, 16168, DOI: 10.12688/wellcomeopenres.16168.2
- 38Leeson, P. D. Molecular inflation, attrition and the rule of five. Adv. Drug Delivery Rev. 2016, 101, 22– 33, DOI: 10.1016/j.addr.2016.01.018[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFCrt7k%253D&md5=7e31a4390c28a0f203f2254bcfb754afMolecular inflation, attrition and the rule of fiveLeeson, Paul D.Advanced Drug Delivery Reviews (2016), 101 (), 22-33CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Physicochem. properties underlie all aspects of drug action and are crit. for soly., permeability and successful formulation. Specific physicochem. properties shown to be relevant to oral drugs are size, lipophilicity, ionisation, hydrogen bonding, polarity, aromaticity and shape. The rule of 5 (Ro5) and subsequent studies have raised awareness of the importance of compd. quality amongst bioactive mols. Lipophilicity, probably the most important phys. property of oral drugs, has on av. changed little over time in oral drugs, until increases in drugs published after 1990. In contrast other mol. properties such as av. size have increased significantly. Factors influencing property inflation include the targets pursued, where antivirals frequently violate the Ro5, risk/benefit considerations, and variable drug discovery practices. The compds. published in patents from the pharmaceutical industry are on av. larger, more lipophilic and less complex than marketed oral drugs. The variation between individual companies' patented compds. is due to different practices and not to the targets pursued. Overall, there is demonstrable phys. property attrition in moving from patents to candidate drugs to marketed drugs. The pharmaceutical industry's recent poor productivity has been due, in part, to progression of mols. that are unable to unambiguously test clin. efficacy, and attrition can therefore be improved by ensuring candidate drug quality is 'fit for purpose.' The combined ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of many marketed drugs are optimized relative to other mols. acting at the same target. Application of LLE in optimization can help identify improved leads, even with challenging targets that seem to require lipophilic ligands. Because of their targets, some projects may need to pursue 'beyond Ro5' physicochem. space; such projects will require non-std. lead generation and optimization and should not dominate in a well-balanced portfolio. Compd. quality is controllable by lead selection and optimization and should not be a cause of clin. failure.
- 39Leeson, P. D.; Young, R. J. Molecular Property Design: Does Everyone Get It?. ACS Med. Chem. Lett. 2015, 6, 722– 725, DOI: 10.1021/acsmedchemlett.5b00157[ACS Full Text], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptVGksr4%253D&md5=5a807a8d049ce8cf4adc186891a9234dMolecular Property Design: Does Everyone Get It?Leeson, Paul D.; Young, Robert J.ACS Medicinal Chemistry Letters (2015), 6 (7), 722-725CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A review. The principles of mol. property optimization in drug design have been understood for decades, yet much drug discovery activity today is conducted at the periphery of historical druglike property space. Lead optimization trajectories aimed at reducing physicochem. risk, assisted by ligand efficiency metrics, could help to reduce clin. attrition rates.
- 40Young, R. J.; Leeson, P. D. Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations. J. Med. Chem. 2018, 61, 6421– 6467, DOI: 10.1021/acs.jmedchem.8b00180[ACS Full Text], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXntVCmu7Y%253D&md5=f040ef02d161e070bb5021fde1585e66Mapping the Efficiency and Physicochemical Trajectories of Successful OptimizationsYoung, Robert J.; Leeson, Paul D.Journal of Medicinal Chemistry (2018), 61 (15), 6421-6467CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The practices and tactics employed in successful optimizations are examd., judged from the trajectories of ligand efficiency and property evolution. A wide range of targets is analyzed, encompassing a variety of hit finding methods (HTS, fragments, encoded library technol.) and types of mols., including those beyond the rule of five. The wider employment of efficiency metrics and lipophilicity control is evident in contemporary practice and the impact on quality demonstrable. What is clear is that while targets are different, successful mols. are almost invariably among the most efficient for their target, even at the extremes. Trajectory mapping, based on principles rather than rules, is useful in assessing quality and progress in optimizations while benchmarking against competitors and assessing property-dependent risks.
- 41Agoni, C.; Olotu, F. A.; Ramharack, P.; Soliman, M. E. Druggability and drug-likeness concepts in drug design: are biomodelling and predictive tools having their say?. J. Mol. Model 2020, 26, 120, DOI: 10.1007/s00894-020-04385-6[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXptVGrt7w%253D&md5=41203c0c37710955e899391bf0baf38cDruggability and drug-likeness concepts in drug design: are biomodelling and predictive tools having their say?Agoni, Clement; Olotu, Fisayo A.; Ramharack, Pritika; Soliman, Mahmoud E.Journal of Molecular Modeling (2020), 26 (6), 120CODEN: JMMOFK; ISSN:0948-5023. (Springer)A review. Abstr.: The drug discovery process typically involves target identification and design of suitable drug mols. against these targets. Despite decades of exptl. investigations in the drug discovery domain, about 96% overall failure rate has been recorded in drug development due to the "undruggability" of various identified disease targets, in addn. to other challenges. Likewise, the high attrition rate of drug candidates in the drug discovery process has also become an enormous challenge for the pharmaceutical industry. To alleviate this neg. outlook, new trends in drug discovery have emerged. By drifting away from exptl. research methods, computational tools and big data are becoming valuable in the prediction of biol. target druggability and the drug-likeness of potential therapeutic agents. These tools have proven to be useful in saving time and reducing research costs. As with any emerging technique, however, controversial opinions have been presented regarding the validation of predictive computational tools. To address the challenges assocd. with these varying opinions, this review attempts to highlight the principles of druggability and drug-likeness and their recent advancements in the drug discovery field. Herein, we present the different computational tools and their reliability of predictive anal. in the drug discovery domain. We believe that this report would serve as a comprehensive guide towards computational-oriented drug discovery research. Graphical abstractHighlights of methods for assessing the druggability of biol. targets [graphic not available: see fulltext].
- 42Favuzza, P.; de Lera Ruiz, M.; Thompson, J. K.; Triglia, T.; Ngo, A.; Steel, R. W. J.; Vavrek, M.; Christensen, J.; Healer, J.; Boyce, C.; Guo, Z.; Hu, M.; Khan, T.; Murgolo, N.; Zhao, L.; Penington, J. S.; Reaksudsan, K.; Jarman, K.; Dietrich, M. H.; Richardson, L.; Guo, K. Y.; Lopaticki, S.; Tham, W. H.; Rottmann, M.; Papenfuss, T.; Robbins, J. A.; Boddey, J. A.; Sleebs, B. E.; Sabroux, H. J.; McCauley, J. A.; Olsen, D. B.; Cowman, A. F. Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle. Cell Host Microbe 2020, 27, 642– 658, DOI: 10.1016/j.chom.2020.02.005[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXktlarsrc%253D&md5=c54719d969f0e82bb5e91a7ae9176e7aDual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life CycleFavuzza, Paola; de Lera Ruiz, Manuel; Thompson, Jennifer K.; Triglia, Tony; Ngo, Anna; Steel, Ryan W. J.; Vavrek, Marissa; Christensen, Janni; Healer, Julie; Boyce, Christopher; Guo, Zhuyan; Hu, Mengwei; Khan, Tanweer; Murgolo, Nicholas; Zhao, Lianyun; Penington, Jocelyn Sietsma; Reaksudsan, Kitsanapong; Jarman, Kate; Dietrich, Melanie H.; Richardson, Lachlan; Guo, Kai-Yuan; Lopaticki, Sash; Tham, Wai-Hong; Rottmann, Matthias; Papenfuss, Tony; Robbins, Jonathan A.; Boddey, Justin A.; Sleebs, Brad E.; Sabroux, Helene Jousset; McCauley, John A.; Olsen, David B.; Cowman, Alan F.Cell Host & Microbe (2020), 27 (4), 642-658.e12CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addn., WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.
- 43De Rycker, M.; Baragana, B.; Duce, S. L.; Gilbert, I. H. Challenges and recent progress in drug discovery for tropical diseases. Nature 2018, 559, 498– 506, DOI: 10.1038/s41586-018-0327-4[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtl2jt7zP&md5=3bc57ce68776462cf6a053efa276a989Challenges and recent progress in drug discovery for tropical diseasesDe Rycker, Manu; Baragana, Beatriz; Duce, Suzanne L.; Gilbert, Ian H.Nature (London, United Kingdom) (2018), 559 (7715), 498-506CODEN: NATUAS; ISSN:0028-0836. (Nature Research)Infectious tropical diseases have a huge effect in terms of mortality and morbidity, and impose a heavy economic burden on affected countries. These diseases predominantly affect the world's poorest people. Currently available drugs are inadequate for the majority of these diseases, and there is an urgent need for new treatments. This Review discusses some of the challenges involved in developing new drugs to treat these diseases and highlights recent progress. While there have been notable successes, there is still a long way to go.
- 44Alam, M. M.; Sanchez-Azqueta, A.; Janha, O.; Flannery, E. L.; Mahindra, A.; Mapesa, K.; Char, A. B.; Sriranganadane, D.; Brancucci, N. M. B.; Antonova-Koch, Y.; Crouch, K.; Simwela, N. V.; Millar, S. B.; Akinwale, J.; Mitcheson, D.; Solyakov, L.; Dudek, K.; Jones, C.; Zapatero, C.; Doerig, C.; Nwakanma, D. C.; Vázquez, M. J.; Colmenarejo, G.; Lafuente-Monasterio, M. J.; Leon, M. L.; Godoi, P. H. C.; Elkins, J. M.; Waters, A. P.; Jamieson, A. G.; Álvaro, E. F.; Ranford-Cartwright, L. C.; Marti, M.; Winzeler, E. A.; Gamo, F. J.; Tobin, A. B. Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target. Science 2019, 365, eaau1682, DOI: 10.1126/science.aau1682
- 45Schalkwijk, J.; Allman, E. L.; Jansen, P. A. M.; de Vries, L. E.; Verhoef, J. M. J.; Jackowski, S.; Botman, P. N. M.; Beuckens-Schortinghuis, C. A.; Koolen, K. M. J.; Bolscher, J. M.; Vos, M. W.; Miller, K.; Reeves, S. A.; Pett, H.; Trevitt, G.; Wittlin, S.; Scheurer, C.; Sax, S.; Fischli, C.; Angulo-Barturen, I.; Jiménez-Diaz, M. B.; Josling, G.; Kooij, T. W. A.; Bonnert, R.; Campo, B.; Blaauw, R. H.; Rutjes, F.; Sauerwein, R. W.; Llinás, M.; Hermkens, P. H. H.; Dechering, K. J. Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum. Sci. Transl. Med. 2019, 11, eaas9917, DOI: 10.1126/scitranslmed.aas9917
- 46Summers, R. L.; Pasaje, C. F. A.; Pisco, J. P.; Striepen, J.; Luth, M. R.; Kumpornsin, K.; Carpenter, E. F.; Munro, J. T.; Lin, D.; Plater, A.; Punekar, A. S.; Shepherd, A. M.; Shepherd, S. M.; Vanaerschot, M.; Murithi, J. M.; Rubiano, K.; Akidil, A.; Ottilie, S.; Mittal, N.; Dilmore, A. H.; Won, M.; Mandt, R. E. K.; McGowen, K.; Owen, E.; Walpole, C.; Llinás, M.; Lee, M. C. S.; Winzeler, E. A.; Fidock, D. A.; Gilbert, I. H.; Wirth, D. F.; Niles, J. C.; Baragaña, B.; Lukens, A. K. Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention. Cell Chem. Biol. 2021, DOI: 10.1016/j.chembiol.2021.07.010
- 47Koselny, K.; Green, J.; Favazzo, L.; Glazier, V. E.; DiDone, L.; Ransford, S.; Krysan, D. J. Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase. ACS Infect. Dis. 2016, 2, 268– 280, DOI: 10.1021/acsinfecdis.5b00134[ACS Full Text], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivFOmur4%253D&md5=7cbbf24d6b9d80867c4a66dea648e750Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA SynthetaseKoselny, Kristy; Green, Julianne; Favazzo, Lacey; Glazier, Virginia E.; DiDone, Louis; Ransford, Shea; Krysan, Damian J.ACS Infectious Diseases (2016), 2 (4), 268-280CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)AR-12/OSU-03012 is an antitumor celecoxib-deriv. that has progressed to Phase I clin. trial as an anticancer agent and has activity against a no. of infectious agents including fungi, bacteria and viruses. However, the mechanism of these activities has remained unclear. Based on a chem.-genetic profiling approach in yeast, we have found that AR-12 is an ATP-competitive, time-dependent inhibitor of yeast acetyl CoA synthetase. AR-12-treated fungal cells show phenotypes consistent with the genetic redn. of acetyl CoA synthetase activity, including induction of autophagy, decreased histone acetylation, and loss of cellular integrity. In addn., AR-12 is a weak inhibitor of human acetyl CoA synthetase ACCS2. Acetyl CoA synthetase activity is essential in many fungi and parasites. In contrast, acetyl CoA is primarily synthesized by an alternate enzyme, ATP-citrate lyase, in mammalian cells. Taken together, our results indicate that AR-12 is a non-nucleoside acetyl CoA synthetase inhibitor and that acetyl CoA synthetase may be a feasible antifungal drug target.
- 48Gisselberg, J. E.; Herrera, Z.; Orchard, L. M.; Llinás, M.; Yeh, E. Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding Site. Cell Chem. Biol. 2018, 25, 185– 193, DOI: 10.1016/j.chembiol.2017.11.010[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVehtL3M&md5=ca3af32ced2ff0c07551e08932766858Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding SiteGisselberg, Jolyn E.; Herrera, Zachary; Orchard, Lindsey M.; Llinas, Manuel; Yeh, EllenCell Chemical Biology (2018), 25 (2), 185-193.e5CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)The bifunctional farnesyl/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key branchpoint enzyme in isoprenoid biosynthesis in Plasmodium falciparum (malaria) parasites. PfFPPS/GGPPS is a validated, high-priority antimalarial drug target. Unfortunately, current bisphosphonate drugs that inhibit FPPS and GGPPS enzymes by acting as a diphosphate substrate analog show poor bioavailability and selectivity for PfFPPS/GGPPS. We identified a new non-bisphosphonate compd., MMV019313, which is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes of inhibition. Mol. docking indicated that MMV019313 did not bind previously characterized substrate sites in PfFPPS/GGPPS. Our finding uncovers a new, selective small-mol. binding site in this important antimalarial drug target with superior druggability compared with the known inhibitor site and sets the stage for the development of Plasmodium-specific FPPS/GGPPS inhibitors.
- 49Jordão, F. M.; Gabriel, H. B.; Alves, J. M.; Angeli, C. B.; Bifano, T. D.; Breda, A.; de Azevedo, M. F.; Basso, L. A.; Wunderlich, G.; Kimura, E. A.; Katzin, A. M. Cloning and characterization of bifunctional enzyme farnesyl diphosphate/geranylgeranyl diphosphate synthase from Plasmodium falciparum. Malar. J. 2013, 12, 184, DOI: 10.1186/1475-2875-12-184[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVejtr7K&md5=536a7f8b59fbce904afeea70e3ab03baCloning and characterization of bifunctional enzyme farnesyl diphosphate/geranylgeranyl diphosphate synthase from Plasmodium falciparumJordao, Fabiana M.; Gabriel, Heloisa B.; Alves, Joao M. P.; Angeli, Claudia B.; Bifano, Thais D.; Breda, Ardala; de Azevedo, Mauro F.; Basso, Luiz A.; Wunderlich, Gerhard; Kimura, Emilia A.; Katzin, Alejandro M.Malaria Journal (2013), 12 (), 184CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)Background: Isoprenoids are the most diverse and abundant group of natural products. In Plasmodium falciparum, isoprenoid synthesis proceeds through the Me erythritol diphosphate pathway and the products are further metabolized by farnesyl diphosphate synthase (FPPS), turning this enzyme into a key branch point of the isoprenoid synthesis. Changes in FPPS activity could alter the flux of isoprenoid compds. downstream of FPPS and, hence, play a central role in the regulation of a no. of essential functions in Plasmodium parasites. Methods: The isolation and cloning of gene PF3D7_18400 was done by amplification from cDNA from mixed stage parasites of P. falciparum. After sequencing, the fragment was subcloned in pGEX2T for recombinant protein expression. To verify if the PF3D7_1128400 gene encodes a functional rPfFPPS protein, its catalytic activity was assessed using the substrate [4-14C] isopentenyl diphosphate and three different allylic substrates: dimethylallyl diphosphate, geranyl diphosphate or farnesyl diphosphate. The reaction products were identified by thin layer chromatog. and reverse phase high-performance liq. chromatog. To confirm the product spectrum formed of rPfFPPS, isoprenic compds. were also identified by mass spectrometry. Apparent kinetic consts. KM and Vmax for each substrate were detd. by Michaelis-Menten; also, inhibition assays were performed using risedronate. Results: The expressed protein of P. falciparum FPPS (rPfFPPS) catalyzes the synthesis of farnesyl diphosphate, as well as geranylgeranyl diphosphate, being therefore a bifunctional FPPS/geranylgeranyl diphosphate synthase (GGPPS) enzyme. The apparent KM values for the substrates dimethylallyl diphosphate, geranyl diphosphate and farnesyl diphosphate were, resp., 68 ± 5 μM, 7.8 ± 1.3 μM and 2.06 ± 0.4 μM. The protein is expressed constitutively in all intra-erythrocytic stages of P. falciparum, demonstrated by using transgenic parasites with a haemagglutinin-tagged version of FPPS. Also, the present data demonstrate that the recombinant protein is inhibited by risedronate. Conclusions: The rPfFPPS is a bifunctional FPPS/GGPPS enzyme and the structure of products FOH and GGOH were confirmed mass spectrometry. Plasmodial FPPS represents a potential target for the rational design of chemotherapeutic agents to treat malaria.
- 50Yoo, E.; Schulze, C. J.; Stokes, B. H.; Onguka, O.; Yeo, T.; Mok, S.; Gnädig, N. F.; Zhou, Y.; Kurita, K.; Foe, I. T.; Terrell, S. M.; Boucher, M. J.; Cieplak, P.; Kumpornsin, K.; Lee, M. C. S.; Linington, R. G.; Long, J. Z.; Uhlemann, A. C.; Weerapana, E.; Fidock, D. A.; Bogyo, M. The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites. Cell Chem. Biol. 2020, 27, 143– 157, DOI: 10.1016/j.chembiol.2020.01.001[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFyitb0%253D&md5=236485f5855092e9e7e2acde4d3b9ac4The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum ParasitesYoo, Euna; Schulze, Christopher J.; Stokes, Barbara H.; Onguka, Ouma; Yeo, Tomas; Mok, Sachel; Gnadig, Nina F.; Zhou, Yani; Kurita, Kenji; Foe, Ian T.; Terrell, Stephanie M.; Boucher, Michael J.; Cieplak, Piotr; Kumpornsin, Krittikorn; Lee, Marcus C. S.; Linington, Roger G.; Long, Jonathan Z.; Uhlemann, Anne-Catrin; Weerapana, Eranthie; Fidock, David A.; Bogyo, MatthewCell Chemical Biology (2020), 27 (2), 143-157.e5CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homol. to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metab. Resistance selections yielded parasites that showed only minor redns. in sensitivity and that acquired mutations in a PRELI domain-contg. protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets.
- 51Schulze, C. J.; Navarro, G.; Ebert, D.; DeRisi, J.; Linington, R. G. Salinipostins A-K, long-chain bicyclic phosphotriesters as a potent and selective antimalarial chemotype. J. Org. Chem. 2015, 80, 1312– 20, DOI: 10.1021/jo5024409[ACS Full Text], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosVCktw%253D%253D&md5=83525e8326d755cd99f9bc90a072305cSalinipostins A-K, Long-Chain Bicyclic Phosphotriesters as a Potent and Selective Antimalarial ChemotypeSchulze, Christopher J.; Navarro, Gabriel; Ebert, Daniel; DeRisi, Joseph; Linington, Roger G.Journal of Organic Chemistry (2015), 80 (3), 1312-1320CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Despite significant advances in antimalarial chemotherapy over the past 30 years, development of resistance to frontline drugs remains a significant challenge that limits efforts to eradicate the disease. We now report the discovery of a new class of antimalarials, salinipostins A-K, with low nanomolar potencies and high selectivity indexes against mammalian cells (salinipostin A: Plasmodium falciparum EC50 50 nM, HEK293T cytotoxicity EC50 > 50 μM). These compds. were isolated from a marine-derived Salinospora sp. bacterium and contain a bicyclic phosphotriester core structure, which is a rare motif among natural products. This scaffold differs significantly from the structures of known antimalarial compds. and represents a new lead structure for the development of therapeutic targets in malaria. Examn. of the growth stage specificity of salinipostin A indicates that it exhibits growth stage-specific effects that differ from compds. that inhibit heme polymn., while resistance selection expts. were unable to identify parasite populations that exhibited significant resistance against this compd. class.
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- 53Wong, C. H.; Siah, K. W.; Lo, A. W. Estimation of clinical trial success rates and related parameters. Biostatistics 2019, 20, 273– 286, DOI: 10.1093/biostatistics/kxx069[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mvmslejsw%253D%253D&md5=95204fe37aec420da08b3401189e3ba5Estimation of clinical trial success rates and related parametersWong Chi Heem; Siah Kien Wei; Lo Andrew WBiostatistics (Oxford, England) (2019), 20 (2), 273-286 ISSN:.Previous estimates of drug development success rates rely on relatively small samples from databases curated by the pharmaceutical industry and are subject to potential selection biases. Using a sample of 406 038 entries of clinical trial data for over 21 143 compounds from January 1, 2000 to October 31, 2015, we estimate aggregate clinical trial success rates and durations. We also compute disaggregated estimates across several trial features including disease type, clinical phase, industry or academic sponsor, biomarker presence, lead indication status, and time. In several cases, our results differ significantly in detail from widely cited statistics. For example, oncology has a 3.4% success rate in our sample vs. 5.1% in prior studies. However, after declining to 1.7% in 2012, this rate has improved to 2.5% and 8.3% in 2014 and 2015, respectively. In addition, trials that use biomarkers in patient-selection have higher overall success probabilities than trials without biomarkers.
- 54Wang, J.; Yazdani, S.; Han, A.; Schapira, M. Structure-based view of the druggable genome. Drug Discovery Today 2020, 25, 561– 567, DOI: 10.1016/j.drudis.2020.02.006[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjs12rtbo%253D&md5=7c85eee4b0bb92e0801ea781c067cd9aStructure-based view of the druggable genomeWang, Jiayan; Yazdani, Setayesh; Han, Ana; Schapira, MatthieuDrug Discovery Today (2020), 25 (3), 561-567CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. International efforts are underway to develop chem. probes for specific protein families, and a 'Target 2035' call to expand these efforts towards a comprehensive chem. coverage of the druggable human genome was recently announced. But what is the druggable genome. Here, we systematically review structures of proteins bound to drug-like ligands available from the Protein Data Bank (PDB) and use ligand desolvation upon binding as a druggability metric to draw a landscape of the human druggable genome. The vast majority of druggable protein families, including some highly populated and disease-assocd. families, are almost orphan of small-mol. ligands. We propose a list of 46 druggable domains representing 3440 human proteins that could be the focus of large chem. probe discovery efforts.
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- 57Jomaa, H.; Wiesner, J.; Sanderbrand, S.; Altincicek, B.; Weidemeyer, C.; Hintz, M.; Turbachova, I.; Eberl, M.; Zeidler, J.; Lichtenthaler, H. K.; Soldati, D.; Beck, E. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 1999, 285, 1573– 1576, DOI: 10.1126/science.285.5433.1573[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXlslOqsrY%253D&md5=3b12e27cdd89da3155de8099c725f3b9Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugsJomaa, Hassan; Wiesner, Jochen; Sanderbrand, Silke; Altincicek, Boran; Weidemeyer, Claus; Hintz, Martin; Turbachova, Ivana; Eberl, Matthias; Zeidler, Johannes; Lichtenthaler, Hartmut K.; Soldati, Dominique; Beck, EwaldScience (Washington, D. C.) (1999), 285 (5433), 1573-1576CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A mevalonate-independent pathway of isoprenoid biosynthesis present in Plasmodium falciparum was shown to represent an effective target for chemotherapy of malaria. This pathway includes 1-deoxy-D-xylulose 5-phosphate (DOXP) as a key metabolite. The presence of two genes encoding the enzymes DOXP synthase and DOXP reductoisomerase suggests that isoprenoid biosynthesis in P. falciparum depends on the DOXP pathway. This pathway is probably located in the apicoplast. The recombinant P. falciparum DOXP reductoisomerase was inhibited by fosmidomycin and its deriv., FR-900098. Both drugs suppressed the in vitro growth of multidrug-resistant P. falciparum strains. After therapy with these drugs, mice infected with the rodent malaria parasite P. vinckei were cured.
- 58Yeh, E.; DeRisi, J. L. Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum. PLoS Biol. 2011, 9, e1001138, DOI: 10.1371/journal.pbio.1001138[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1WrtLbN&md5=7495d8087b18cba682c62077eabda432Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparumYeh, Ellen; DeRisi, Joseph L.PLoS Biology (2011), 9 (8), e1001138CODEN: PBLIBG; ISSN:1545-7885. (Public Library of Science)Plasmodium spp. parasites harbor an unusual plastid organelle called the apicoplast. Due to its prokaryotic origin and essential function, the apicoplast is a key target for development of new anti-malarials. Over 500 proteins are predicted to localize to this organelle and several prokaryotic biochem. pathways have been annotated, yet the essential role of the apicoplast during human infection remains a mystery. Previous work showed that treatment with fosmidomycin, an inhibitor of non-mevalonate isoprenoid precursor biosynthesis in the apicoplast, inhibits the growth of blood-stage P. falciparum. Here, the authors demonstrate that fosmidomycin inhibition can be chem. rescued by supplementation with isopentenyl pyrophosphate (IPP), the pathway product. Surprisingly, IPP supplementation also completely reverses death following treatment with antibiotics that cause loss of the apicoplast. Antibiotic-treated parasites rescued with IPP over multiple cycles specifically lose their apicoplast genome and fail to process or localize organelle proteins, rendering them functionally apicoplast-minus. Despite the loss of this essential organelle, these apicoplast-minus auxotrophs can be grown indefinitely in asexual blood stage culture but are entirely dependent on exogenous IPP for survival. These findings indicate that isoprenoid precursor biosynthesis is the only essential function of the apicoplast during blood-stage growth. Moreover, apicoplast-minus P. falciparum strains will be a powerful tool for further investigation of apicoplast biol. as well as drug and vaccine development.
- 59Uddin, T.; McFadden, G. I.; Goodman, C. D. Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites. Antimicrob. Agents Chemother. 2018, 62, e01161-17, DOI: 10.1128/AAC.01161-17
- 60Yu, M.; Kumar, T. R.; Nkrumah, L. J.; Coppi, A.; Retzlaff, S.; Li, C. D.; Kelly, B. J.; Moura, P. A.; Lakshmanan, V.; Freundlich, J. S.; Valderramos, J. C.; Vilcheze, C.; Siedner, M.; Tsai, J. H.; Falkard, B.; Sidhu, A. B.; Purcell, L. A.; Gratraud, P.; Kremer, L.; Waters, A. P.; Schiehser, G.; Jacobus, D. P.; Janse, C. J.; Ager, A.; Jacobs, W. R., Jr.; Sacchettini, J. C.; Heussler, V.; Sinnis, P.; Fidock, D. A. The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites. Cell Host Microbe 2008, 4, 567– 78, DOI: 10.1016/j.chom.2008.11.001[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlKqtQ%253D%253D&md5=8166213984c5cfc1589764054c68e43cThe fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasitesYu, Min; Kumar, T. R. Santha; Nkrumah, Louis J.; Coppi, Alida; Retzlaff, Silke; Li, Celeste D.; Kelly, Brendan J.; Moura, Pedro A.; Lakshmanan, Viswanathan; Freundlich, Joel S.; Valderramos, Juan-Carlos; Vilcheze, Catherine; Siedner, Mark; Tsai, Jennifer H.-C.; Falkard, Brie; Sidhu, Amar bir Singh; Purcell, Lisa A.; Gratraud, Paul; Kremer, Laurent; Waters, Andrew P.; Schiehser, Guy; Jacobus, David P.; Janse, Chris J.; Ager, Arba; Jacobs, William R., Jr.; Sacchettini, James C.; Heussler, Volker; Sinnis, Photini; Fidock, David A.Cell Host & Microbe (2008), 4 (6), 567-578CODEN: CHMECB; ISSN:1931-3128. (Cell Press)The fatty acid synthesis type II pathway has received considerable interest as a candidate therapeutic target in Plasmodium falciparum asexual blood-stage infections. This apicoplast-resident pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chem. and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial FabI. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood-stage growth. In contrast, mosquito-derived, FabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver-stage development in vitro. This defect is characterized by an inability to form intrahepatic merosomes that normally initiate blood-stage infections. These data illuminate key differences between liver- and blood-stage parasites in their requirements for host vs. de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions.
- 61Vaughan, A. M.; O’Neill, M. T.; Tarun, A. S.; Camargo, N.; Phuong, T. M.; Aly, A. S.; Cowman, A. F.; Kappe, S. H. Type II fatty acid synthesis is essential only for malaria parasite late liver stage development. Cell. Microbiol. 2009, 11, 506– 520, DOI: 10.1111/j.1462-5822.2008.01270.x[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXivVejsrg%253D&md5=f2b83d0fe99674f0ae4e721a7a0a8f8dType II fatty acid synthesis is essential only for malaria parasite late liver stage developmentVaughan, Ashley M.; O'Neill, Matthew T.; Tarun, Alice S.; Camargo, Nelly; Phuong, Thuan M.; Aly, Ahmed S. I.; Cowman, Alan F.; Kappe, Stefan H. I.Cellular Microbiology (2009), 11 (3), 506-520CODEN: CEMIF5; ISSN:1462-5814. (Wiley-Blackwell)Intracellular malaria parasites require lipids for growth and replication. They possess a prokaryotic type II fatty acid synthesis (FAS II) pathway that localizes to the apicoplast plastid organelle and is assumed to be necessary for pathogenic blood stage replication. However, the importance of FAS II throughout the complex parasite life cycle remains unknown. We show in a rodent malaria model that FAS II enzymes localize to the sporozoite and liver stage apicoplast. Targeted deletion of FabB/F, a crit. enzyme in fatty acid synthesis, did not affect parasite blood stage replication, mosquito stage development and initial infection in the liver. This was confirmed by knockout of FabZ, another crit. FAS II enzyme. However, FAS II-deficient Plasmodium yoelii liver stages failed to form exo-erythrocytic merozoites, the invasive stage that first initiates blood stage infection. Furthermore, deletion of FabI in the human malaria parasite Plasmodium falciparum did not show a redn. in asexual blood stage replication in vitro. Malaria parasites therefore depend on the intrinsic FAS II pathway only at one specific life cycle transition point, from liver to blood.
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