Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity

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This article references 84 other publications.

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   Trends in parasitology (2018), 34 (9), 735-746 ISSN:.

   Malaria remains a major global health challenge. Appropriate use of current antimalarial tools has reduced the disease burden, but morbidity and mortality remain unacceptably high. It is widely accepted that, to achieve long-term control/eradication, it will be necessary to use interventions that inhibit the transmission of parasites to mosquitoes - these tools are termed transmission-blocking interventions (TBIs). This article aims to outline the rationale for the development of TBIs, with a focus on transmission-blocking drugs and (parasite-derived) transmission-blocking vaccines. We describe and summarise the current status of each of these intervention classes and attempt to identify future requirements in development, with a focus on the challenges of establishing each method within an integrated malarial control programme in the future.

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   Total cell protein concentration as an evolutionary constraint on the metabolic control distribution in cells

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   Cell protein occupies 15-35% of cell vol. This level is argued to be the max. compatible with cell function. Because of this constraint, selection pressure during evolution is likely to have maximized pathway fluxes for min. total protein level. Pathways optimized in this way are shown to have the following characteristics: (1) the simple flux control coeffs. of all enzymes are equal, (2) the normal flux control coeffs. depend on the relative kinetic consts. of the enzymes, such that enzymes with low specific activity are present at relatively high levels and have high flux control, (3) the normal flux control coeffs. are proportional to enzyme levels. A single rate-limiting step located at the first step in a pathway is likely to be inefficient in terms of protein levels, and the major metabolic pathways are therefore expected to have control distributed throughout the pathway. This has important implications for metabolic control.

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   Levinthal's paradox

   Zwanzig, Robert; Szabo, Attila; Bagchi, Biman

   Proceedings of the National Academy of Sciences of the United States of America (1992), 89 (1), 20-2CODEN: PNASA6; ISSN:0027-8424.

   Levinthal's paradox is that finding the native folded state of a protein by a random search among all possible configurations can take an enormously long time. Yet proteins can fold in seconds or less. Math. anal. of a simple model shows that a small and phys. reasonable energy bias against locally unfavorable configurations, of the order of a few kT, can reduce Levinthal's time to a biol. significant size.

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   A review. Most proteins must fold into defined 3-dimensional structures to gain functional activity. However, in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of mol. chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein mols. are highly dynamic, const. chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathol. states may spring from a detailed understanding of the pathways underlying proteome maintenance.

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   Statistical mechanics of kinetic proofreading in protein folding in vivo

   Gulukota, Kamalakar; Wolynes, Peter G.

   Proceedings of the National Academy of Sciences of the United States of America (1994), 91 (20), 9292-6CODEN: PNASA6; ISSN:0027-8424.

   The statistical energy landscape picture of protein folding has led to the understanding that the energy landscape must have guiding forces leading to a protein folding funnel to avoid the Levinthal paradox in vitro. Since folding in vivo often requires the action of chaperone mols. and ATP hydrolysis, the authors must ask whether folding in a system maintained away from equil. can avoid the Levinthal paradox in other ways. The authors describe a model of the action of chaperone mols. in protein folding in vivo on the basis of a repetitive cycle of binding and unbinding, allowing the possibility of kinetic proofreading. The authors also study models in which chaperone binding is locally biased, depending on the similarity of the conformation to the native one. The authors show that while kinetic proofreading can modestly facilitate folding, it is insufficient by itself to overcome the Levinthal paradox. Such kinetic proofreading with biasing can provide the nonequil. analog of a folding funnel and greatly enhance folding yields and speed up folding.

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    Jortzik, E. and Becker, K. (2012) Thioredoxin and Glutathione Systems in Plasmodium Falciparum. Int. J. Med. Microbiol. 302 (4–5), 187– 194,  DOI: 10.1016/j.ijmm.2012.07.007

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    Thioredoxin and glutathione systems in Plasmodium falciparum

    Jortzik, Esther; Becker, Katja

    International Journal of Medical Microbiology (2012), 302 (4-5), 187-194CODEN: IMEMFV; ISSN:1438-4221. (Elsevier GmbH)

    A review. Despite a 50% decrease in malaria infections between 2000 and 2010, malaria is still one of the three leading infectious diseases with an estd. 216 million cases worldwide in 2010. More than 90% of all malaria infections were caused by Plasmodium falciparum, a unicellular eukaryotic parasite that faces oxidative stress challenges while developing in Anopheles mosquitoes and humans. Reactive oxygen and nitrogen species threatening the parasite are either endogenously produced by heme derived from Hb degrdn. or they are from exogenous sources such as the host immune defense. In order to maintain the intracellular redox balance, P. falciparum employs a complex thioredoxin and glutathione system based on the thioredoxin reductase/thioredoxin and glutathione reductase/glutathione couples. P. falciparum thioredoxin reductase reduces thioredoxin and a range of low mol. wt. compds., while glutathione reductase is highly specific for its substrate glutathione disulfide. Since Plasmodium spp. lack catalase and a classical glutathione peroxidase, their redox balance depends on a complex set of five peroxiredoxins differentially located in the cytosol, apicoplast, mitochondria, and nucleus with partially overlapping substrate preferences. Moreover, P. falciparum employs a set of members belonging to the thioredoxin superfamily such as three thioredoxins, two thioredoxin-like proteins, a dithiol and three monocysteine glutaredoxins, and a redox-active plasmoredoxin with largely redundant functions. This review aims at summarizing our current knowledge on the functional redox networks of the malaria parasite P. falciparum.

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    Becker, K., Tilley, L., Vennerstrom, J. L., Roberts, D., Rogerson, S., and Ginsburg, H. (2004) Oxidative Stress in Malaria Parasite-Infected Erythrocytes: Host - Parasite Interactions. Int. J. Parasitol. 34 (2), 163– 189,  DOI: 10.1016/j.ijpara.2003.09.011

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    Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions

    Becker, Katja; Tilley, Leann; Vennerstrom, Jonathan L.; Roberts, David; Rogerson, Stephen; Ginsburg, Hagai

    International Journal for Parasitology (2004), 34 (2), 163-189CODEN: IJPYBT; ISSN:0020-7519. (Elsevier Science Ltd.)

    A review. Experimenta naturae, like the glucose-6-phosphate dehydrogenase deficiency, indicate that malaria parasites are highly susceptible to alterations in the redox equil. This offers a great potential for the development of urgently required novel chemotherapeutic strategies. However, the relationship between the redox status of malarial parasites and that of their host is complex. In this review article the authors summarize the presently available knowledge on sources and detoxification pathways of reactive oxygen species in malaria parasite-infected red cells, on clin. aspects of redox metab. and redox-related mechanisms of drug action as well as future prospects for drug development. As delineated below, alterations in redox status contribute to disease manifestation including sequestration, cerebral pathol., anemia, respiratory distress, and placental malaria. Studying hemoglobinopathies, like thalassemias and sickle cell disease, and other red cell defects that provide protection against malaria allows insights into this fine balance of redox interactions. The host immune response to malaria involves phagocytosis as well as the prodn. of nitric oxide and oxygen radicals that form part of the host defense system and also contribute to the pathol. of the disease. Hb degrdn. by the malarial parasite produces the redox active byproducts, free hem and H2O2, conferring oxidative insult on the host cell. However, the parasite also supplies antioxidant moieties to the host and possesses an efficient enzymic antioxidant defense system including glutathione- and thioredoxin-dependent proteins. Mechanistic and structural work on these enzymes might provide a basis for targeting the parasite. Indeed, a no. of currently used drugs, esp. the endoperoxide antimalarials, appear to act by increasing oxidant stress, and novel drugs such as peroxidic compds. and anthroquinones are being developed.

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12. 12

    Acharya, P., Kumar, R., and Tatu, U. (2007) Chaperoning a Cellular Upheaval in Malaria: Heat Shock Proteins in Plasmodium Falciparum. Mol. Biochem. Parasitol. 153 (2), 85– 94,  DOI: 10.1016/j.molbiopara.2007.01.009

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    Chaperoning a cellular upheaval in malaria: Heat shock proteins in Plasmodium falciparum

    Acharya, Pragyan; Kumar, Ranjit; Tatu, Utpal

    Molecular & Biochemical Parasitology (2007), 153 (2), 85-94CODEN: MBIPDP; ISSN:0166-6851. (Elsevier Ltd.)

    A review. In addn. to their ability to help newly synthesized proteins to fold, mol. chaperones are also recognized for their participation in cellular processes ranging from protein trafficking, signal transduction, differentiation and development. Novel roles for this group of proteins have come to light through studies on important human pathogens like Leishmania, Trypanosoma as well as Plasmodia species. This review analyzes the authors' current state of knowledge on mol. chaperones in human malarial parasite Plasmodium falciparum. In addn. to a comparative anal. of their structures, complexes, client proteins and functions, a discussion on their potential as vaccine candidates as well as drug targets is also presented. The major chaperone classes of Hsp90, Hsp70, Hsp60 and Hsp40 family are well represented in the malarial parasite. Genomic cataloging of all the parasite chaperone homologs indicates that about 2% of the total no. of genes are dedicated to this function. While Hsp90 and Hsp70 are the most abundantly expressed, the Hsp40 class appears to be the best represented among the 92 chaperones encoded by the parasite genome. Importantly PfHsp70 is considered a potential vaccine candidate and PfHsp90 has been implicated as a drug target against the parasite. Available information suggests fascinating roles for chaperones in the life cycle of the parasite. In addn. to their value as therapeutic targets, the study of chaperones in parasitic systems may likely reveal new principles of chaperone function in biol.

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13. 13

    Pavithra, S. R., Kumar, R., and Tatu, U. (2007) Systems Analysis of Chaperone Networks in the Malarial Parasite Plasmodium Falciparum. PLoS Comput. Biol. 3 (9), 1701– 1715,  DOI: 10.1371/journal.pcbi.0030168

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    Systems analysis of chaperone networks in the malarial parasite Plasmodium falciparum

    Pavithra, Soundara Raghavan; Kumar, Ranjit; Tatu, Utpal

    PLoS Computational Biology (2007), 3 (9), 1701-1715CODEN: PCBLBG; ISSN:1553-7358. (Public Library of Science)

    Mol. chaperones participate in the maintenance of cellular protein homeostasis, cell growth and differentiation, signal transduction, and development. Although a vast body of information is available regarding individual chaperones, few studies have attempted a systems level anal. of chaperone function. In this paper, the authors have constructed a chaperone interaction network for the malarial parasite, Plasmodium falciparum. P. falciparum is responsible for several million deaths every year, and understanding the biol. of the parasite is a top priority. The parasite regularly experiences heat shock as part of its life cycle, and chaperones have often been implicated in parasite survival and growth. To better understand the participation of chaperones in cellular processes, the authors created a parasite chaperone network by combining exptl. interactome data with in silico anal. The authors used interolog mapping to predict protein-protein interactions for parasite chaperones based on the interactions of corresponding human chaperones. This data was then combined with information derived from existing high-throughput yeast two-hybrid assays. Anal. of the network reveals the broad range of functions regulated by chaperones. The network predicts involvement of chaperones in chromatin remodeling, protein trafficking, and cytoadherence. Importantly, it allows the authors to make predictions regarding the functions of hypothetical proteins based on their interactions. It allows the authors to make specific predictions about Hsp70-Hsp40 interactions in the parasite and assign functions to members of the Hsp90 and Hsp100 families. Anal. of the network provides a rational basis for the anti-malarial activity of geldanamycin, a well-known Hsp90 inhibitor. Finally, anal. of the network provides a theor. basis for further expts. designed toward understanding the involvement of this important class of mols. in parasite biol.

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    Dogovski, C., Xie, S. C., Burgio, G., Bridgford, J., Mok, S., McCaw, J. M., Chotivanich, K., Kenny, S., Gnädig, N., Straimer, J., Bozdech, Z., Fidock, D. A., Simpson, J. A., Dondorp, A. M., Foote, S., Klonis, N., and Tilley, L. (2015) Targeting the Cell Stress Response of Plasmodium Falciparum to Overcome Artemisinin Resistance. PLoS Biol. 13 (4), e1002132,  DOI: 10.1371/journal.pbio.1002132

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    Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance

    Dogovski, Con; Xie, Stanley C.; Burgio, Gaetan; Bridgford, Jess; Mok, Sachel; McCaw, James M.; Chotivanich, Kesinee; Kenny, Shannon; Gnadig, Nina; Straimer, Judith; Bozdech, Zbynek; Fidock, David A.; Simpson, Julie A.; Dondorp, Arjen M.; Foote, Simon; Klonis, Nectarios; Tilley, Leann

    PLoS Biology (2015), 13 (4), e1002132/1-e1002132/26CODEN: PBLIBG; ISSN:1545-7885. (Public Library of Science)

    Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs) has emerged, and that the prevalence of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propeller protein. The authors undertook a detailed kinetic anal. of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin). They demonstrate that ART treatment induces growth retardation and an accumulation of ubiquitinated proteins, indicative of a cellular stress response that engages the ubiquitin/proteasome system. They show that resistant parasites exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. The stress response could be targeted by inhibiting the proteasome. Accordingly, clin. used proteasome inhibitors strongly synergize ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type K13. Synergy is also obsd. against Plasmodium berghei in vivo. The authors developed a detailed model of parasite responses that enabled them to infer in vivo parasite clearance profiles from in vitro assessments of ART sensitivity. They provide evidence that the clin. marker of resistance (delayed parasite clearance) is an indirect measure of drug efficacy because of the persistence of unviable parasites with unchanged morphol. in the circulation, and we suggest alternative approaches for the direct measurement of viability. This model predicts that extending current three-day ART treatment courses to four days, or splitting the doses, will efficiently clear resistant parasite infections. This work provides a rationale for improving the detection of ART resistance in the field and for treatment strategies that can be employed in areas with ART resistance.

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    Gosline, S. J. C., Nascimento, M., McCall, L. I., Zilberstein, D., Thomas, D. Y., Matlashewski, G., and Hallett, M. (2011) Intracellular Eukaryotic Parasites Have a Distinct Unfolded Protein Response. PLoS One  DOI: 10.1371/journal.pone.0019118

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    Posfai, D., Eubanks, A. L., Keim, A. I., Lu, K. Y., Wang, G. Z., Hughes, P. F., Kato, N., Haystead, T. A., and Derbyshire, E. R. (2018) Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity. Antimicrob. Agents Chemother. 62 (4), e01799-17  DOI: 10.1128/AAC.01799-17

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    Wang, T., Mäser, P., and Picard, D. (2016) Inhibition of Plasmodium Falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-Carbazoles. J. Med. Chem. 59 (13), 6344– 6352,  DOI: 10.1021/acs.jmedchem.6b00591

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    Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles

    Wang, Tai; Maser, Pascal; Picard, Didier

    Journal of Medicinal Chemistry (2016), 59 (13), 6344-6352CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Malaria caused by the protozoan parasite Plasmodium falciparum (Pf) remains a major public health problem throughout the developing world. One mol. target that should receive more attention is the mol. chaperone Hsp90. It is essential and highly conserved in all eukaryotes, including in protozoan parasites. We have identified an amino-alc. carbazole (N-CBZ) as a PfHsp90-selective inhibitor by virtually docking a large set of antimalarial compds., previously found in a phenotypic screen, into a PfHsp90-specific pocket. By correlating the ability of 30 addnl. N-CBZ derivs. to bind directly to PfHsp90 with their Pf-inhibitory activity, we found that these types of compds. are more likely to inhibit Pf growth if they bind PfHsp90. For plausible targets such as PfHsp90, our workflow may help identifying the mol. target for compds. found by screening large chem. libraries for a desired biol. effect and, conversely, ensuring biol. effectiveness for compds. affecting a particular target.

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    Neckers, L. and Tatu, U. (2008) Molecular Chaperones in Pathogen Virulence: Emerging New Targets for Therapy. Cell Host Microbe 4 (6), 519– 527,  DOI: 10.1016/j.chom.2008.10.011

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    Molecular chaperones in pathogen virulence: Emerging new targets for therapy

    Neckers, Len; Tatu, Utpal

    Cell Host & Microbe (2008), 4 (6), 519-527CODEN: CHMECB; ISSN:1931-3128. (Cell Press)

    A review. Infectious organisms have to cope with demanding and rapidly changing environments during establishment in the host. This is particularly relevant for pathogens that utilize different hosts to complete their life cycle. In addn. to homeotic environmental challenges, other stressful factors, such as oxidative bursts, are often triggered in response to infection. It is not surprising that many successful pathogens have developed robust chaperone systems to conquer the stressful environments in the host. In addn. to discussing ingenious ways by which pathogens have utilized chaperones, the potential of exploiting pathogen chaperones as drug targets is also discussed.

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    Shonhai, A. (2010) Plasmodial Heat Shock Proteins: Targets for Chemotherapy. FEMS Immunol. Med. Microbiol. 58 (1), 61– 74,  DOI: 10.1111/j.1574-695X.2009.00639.x

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    Plasmodial heat shock proteins: targets for chemotherapy

    Shonhai, Addmore

    FEMS Immunology and Medical Microbiology (2010), 58 (1), 61-74CODEN: FIMIEV; ISSN:0928-8244. (Wiley-Blackwell)

    A review. Heat shock proteins act as mol. chaperones, facilitating protein folding in cells of living organisms. Their role is particularly important in parasites because environmental changes assocd. with their life cycles place a strain on protein homeostasis. Not surprisingly, some heat shock proteins are essential for the survival of the most virulent malaria parasite, Plasmodium falciparum. This justifies the need for a greater understanding of the specific roles and regulation of malarial heat shock proteins. Furthermore, heat shock proteins play a major role during invasion of the host by the parasite and mediate in malaria pathogenesis. The identification and development of inhibitor compds. of heat shock proteins has recently attracted attention. This is important, given the fact that traditional antimalarial drugs are increasingly failing, as a consequence of parasite increasing drug resistance. Heat shock protein 90 (Hsp90), Hsp70/Hsp40 partnerships and small heat shock proteins are major malaria drug targets. This review examines the structural and functional features of these proteins that render them ideal drug targets and the challenges of targeting these proteins towards malaria drug design. The major antimalarial compds. that have been used to inhibit heat shock proteins include the antibiotic, geldanamycin, deoxyspergualin and pyrimidinones. The proposed mechanisms of action of these mols. and the pathways they inhibit are discussed.

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    Meshnick, S. R. and Dobson, M. J. (2001) The History of Antimalarial Drugs. Antimalarial Chemotherapy 0, 15– 25,  DOI: 10.1385/1-59259-111-6:15

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    The history of antimalarial drugs

    Meshnick, Steven R.; Dobson, Mary J.

    Antimalarial Chemotherapy (2001), (), 15-25CODEN: 69BXCB ISSN:. (Humana Press Inc.)

    A review providing a brief historical account of the treatment of malaria, as it changes with every new scientific development. The need for new antimalarial drugs is emphasized as resistance to artemisinin and Malarone continue to develop.

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    Achan, J., Talisuna, A. O, Erhart, A., Yeka, A., Tibenderana, J. K, Baliraine, F. N, Rosenthal, P. J, and D'Alessandro, U. (2011) Quinine, an Old Anti-Malarial Drug in a Modern World: Role in the Treatment of Malaria. Malar. J. 10 (1), 144,  DOI: 10.1186/1475-2875-10-144

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    Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria

    Achan, Jane; Talisuna, Ambrose O.; Erhart, Annette; Yeka, Adoke; Tibenderana, James K.; Baliraine, Frederick N.; Rosenthal, Philip J.; D'Alessandro, Umberto

    Malaria Journal (2011), 10 (), 144CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)

    A review. Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings i.v. artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a crit. role in the management of malaria, esp. in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solns. to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance.

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22. 22

    Tu, Y. (2011) The Discovery of Artemisinin (Qinghaosu) and Gifts from Chinese Medicine. Nat. Med. 17 (10), 1217– 1220,  DOI: 10.1038/nm.2471

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    22

    The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine

    Tu, Youyou

    Nature Medicine (New York, NY, United States) (2011), 17 (10), 1217-1220CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)

    Malaria, caused by Plasmodium falciparum, has been a life-threatening disease for thousands of years. After the failure of international attempts to eradicate malaria in the 1950s, the disease rebounded, largely due to the emergence of parasites resistant to the existing antimalarial drugs of the time, such as chloroquine. This created an urgent need for new antimalarial medicines. In 1967, a national project against malaria was set up in China under the leadership of the Project 523 office. My institute quickly became involved in the project and appointed me to be the head of a malaria research group comprising both phytochem. and pharmacol. researchers. Our group of young investigators started working on the extn. and isolation of constituents with possible antimalarial activities from Chinese herbal materials. During the first stage of our work, we investigated more than 2,000 Chinese herb prepns. and identified 640 hits that had possible antimalarial activities. More than 380 exts. obtained from ∼200 Chinese herbs were evaluated against a mouse model of malaria. However, progress was not smooth, and no significant results emerged easily. The turning point came when an Artemisia annua L. ext. showed a promising degree of inhibition against parasite growth. However, this observation was not reproducible in subsequent expts. and appeared to be contradictory to what was recorded in the literature. Seeking an explanation, we carried out an intensive review of the literature. The only ref. relevant to use of qinghao (the Chinese name of Artemisia annua L.) for alleviating malaria symptoms appeared in Ge Hong's A Handbook of Prescriptions for Emergencies: "A handful of qinghao immersed with 2 L of water, wring out the juice and drink it all" (Fig. 1). This sentence gave me the idea that the heating involved in the conventional extn. step we had used might have destroyed the active components, and that extn. at a lower temp. might be necessary to preserve antimalarial activity. Indeed, we obtained much better activity after switching to a lower-temp. procedure. We subsequently sepd. the ext. into its acidic and neutral portions and, at long last, on 4 Oct. 1971, we obtained a nontoxic, neutral ext. that was 100% effective against parasitemia in mice infected with Plasmodium berghei and in monkeys infected with Plasmodium cynomolgi. This finding represented the breakthrough in the discovery of artemisinin.

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23. 23

    Ginsburg, H. and Deharo, E. (2011) A Call for Using Natural Compounds in the Development of New Antimalarial Treatments - an Introduction. Malar. J.  DOI: 10.1186/1475-2875-10-S1-S1

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    There is no corresponding record for this reference.
24. 24

    Cauz, A. C. G., Carretero, G. P. B., Saraiva, G. K. V., Park, P., Mortara, L., Cuccovia, I. M., Brocchi, M., and Gueiros-Filho, F. J. (2019) Violacein Targets the Cytoplasmic Membrane of Bacteria. ACS Infect. Dis. 5 (4), 539– 549,  DOI: 10.1021/acsinfecdis.8b00245

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    24

    Violacein Targets the Cytoplasmic Membrane of Bacteria

    Cauz, Ana C. G.; Carretero, Gustavo P. B.; Saraiva, Greice K. V.; Park, Peter; Mortara, Laura; Cuccovia, Iolanda M.; Brocchi, Marcelo; Gueiros-Filho, Frederico J.

    ACS Infectious Diseases (2019), 5 (4), 539-549CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)

    Violacein is a tryptophan-derived purple pigment produced by environmental bacteria, which displays multiple biol. activities, including strong inhibition of Gram-pos. pathogens. We applied a combination of exptl. approaches to identify the mechanism by which violacein kills Gram-pos. bacteria. Fluorescence microscopy showed that violacein quickly and dramatically permeabilizes Bacillus subtilis and Staphylococcus aureus cells. Cell permeabilization was accompanied by the appearance of visible discontinuities or rips in the cytoplasmic membrane, but it did not affect the cell wall. Using in vitro expts., we showed that violacein binds directly to liposomes made with com. and bacterial phospholipids and perturbs their structure and permeability. Furthermore, mol. dynamics simulations were employed to reveal how violacein inserts itself into lipid bilayers. Thus, our combined results demonstrate that the cytoplasmic membrane is the primary target of violacein in bacteria. The implications of this finding for the development of violacein as a therapeutic agent are discussed.

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25. 25

    Bilsland, E., Tavella, T. A., Krogh, R., Stokes, J. E., Roberts, A., Ajioka, J., Spring, D. R., Andricopulo, A. D., Costa, F. T. M., and Oliver, S. G. (2018) Antiplasmodial and Trypanocidal Activity of Violacein and Deoxyviolacein Produced from Synthetic Operons. BMC Biotechnol. 18 (1), 22,  DOI: 10.1186/s12896-018-0428-z

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    25

    Antiplasmodial and trypanocidal activity of violacein and deoxyviolacein produced from synthetic operons

    Bilsland, Elizabeth; Tavella, Tatyana A.; Krogh, Renata; Stokes, Jamie E.; Roberts, Annabelle; Ajioka, James; Spring, David R.; Andricopulo, Adriano D.; Costa, Fabio T. M.; Oliver, Stephen G.

    BMC Biotechnology (2018), 18 (), 22/1-22/8CODEN: BBMIE6; ISSN:1472-6750. (BioMed Central Ltd.)

    Violacein is a deep violet compd. that is produced by a no. of bacterial species. It is synthesized from tryptophan by a pathway that involves the sequential action of 5 different enzymes (encoded by genes vioA to vioE). Violacein has antibacterial, antiparasitic, and antiviral activities, and also has the potential of inducing apoptosis in certain cancer cells. Here, we describe the construction of a series of plasmids harboring the complete or partial violacein biosynthesis operon and their use to enable prodn. of violacein and deoxyviolacein in E.coli. We performed in vitro assays to det. the biol. activity of these compds. against Plasmodium, Trypanosoma, and mammalian cells. We found that, while deoxyviolacein has a lower activity against parasites than violacein, its toxicity to mammalian cells is insignificant compared to that of violacein. We constructed E. coli strains capable of producing biol. active violacein and related compds., and propose that deoxyviolacein might be a useful starting compd. for the development of antiparasite drugs.

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    Durán, N., Justo, G. Z., Durán, M., Brocchi, M., Cordi, L., Tasic, L., Castro, G. R., and Nakazato, G. (2016) Advances in Chromobacterium Violaceum and Properties of Violacein-Its Main Secondary Metabolite: A Review. Biotechnol. Adv. 34 (5), 1030– 1045,  DOI: 10.1016/j.biotechadv.2016.06.003

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    26

    Advances in Chromobacterium violaceum and properties of violacein-Its main secondary metabolite: A review

    Duran, Nelson; Justo, Giselle Z.; Duran, Marcela; Brocchi, Marcelo; Cordi, Livia; Tasic, Ljubica; Castro, Guillermo R.; Nakazato, Gerson

    Biotechnology Advances (2016), 34 (5), 1030-1045CODEN: BIADDD; ISSN:0734-9750. (Elsevier)

    A review. Chromobacterium violaceum is important in the prodn. of violacein, like other bacteria, such as Alteromonas, Janthinobacterium, Pseudoalteromonas, Duganella, Collimonas and Escherichia. Violacein is a versatile pigment, where it exhibits several biol. activities, and every year, it shows increasing com. interesting uses, esp. for industrial applications in cosmetics, medicines and fabrics. This review on violacein focuses mainly on the last five years of research regarding this target compd. and describes prodn. and importance of quorum sensing in C. violaceum, mechanistic aspects of its biosynthesis, monitoring processes, genetic perspectives, pathogenic effects, antiparasitic and antimicrobial activities, immunomodulatory potential and uses, antitumor potential and industrial applications.

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27. 27

    Lopes, S. C. P., Blanco, Y. C., Justo, G. Z., Nogueira, P. A., Rodrigues, F. L. S., Goelnitz, U., Wunderlich, G., Facchini, G., Brocchi, M., Duran, N., and Costa, F. T. M. (2009) Violacein Extracted from Chromobacterium Violaceum Inhibits Plasmodium Growth in Vitro and in Vivo. Antimicrob. Agents Chemother. 53 (5), 2149– 2152,  DOI: 10.1128/AAC.00693-08

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    27

    Violacein extracted from Chromobacterium violaceum inhibits Plasmodium growth in vitro and in vivo

    Lopes, Stefanie C. P.; Blanco, Yara C.; Justo, Giselle Z.; Nogueira, Paulo A.; Rodrigues, Francisco L. S.; Goelnitz, Uta; Wunderlich, Gerhard; Facchini, Gustavo; Brocchi, Marcelo; Duran, Nelson; Costa, Fabio T. M.

    Antimicrobial Agents and Chemotherapy (2009), 53 (5), 2149-2152CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)

    Violacein is a violet pigment extd. from the gram-neg. bacterium Chromobacterium violaceum. It presents bactericidal, tumoricidal, trypanocidal, and antileishmanial activities. We show that micromolar concns. efficiently killed chloroquine-sensitive and -resistant Plasmodium falciparum strains in vitro; inhibited parasitemia in vivo, even after parasite establishment; and protected Plasmodium chabaudi chabaudi-infected mice from a lethal challenge.

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28. 28

    Gitau, G. W., Mandal, P., Blatch, G. L., Przyborski, J., and Shonhai, A. (2012) Characterisation of the Plasmodium Falciparum Hsp70-Hsp90 Organising Protein (PfHop). Cell Stress Chaperones 17 (2), 191– 202,  DOI: 10.1007/s12192-011-0299-x

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    28

    Characterisation of the Plasmodium falciparum Hsp70-Hsp90 organising protein (PfHop)

    Gitau, Grace W.; Mandal, Pradipta; Blatch, Gregory L.; Przyborski, Jude; Shonhai, Addmore

    Cell Stress & Chaperones (2012), 17 (2), 191-202CODEN: CSCHFG; ISSN:1355-8145. (Springer)

    Malaria is caused by Plasmodium species, whose transmission to vertebrate hosts is facilitated by mosquito vectors. The transition from the cold-blooded mosquito vector to the host represents physiol. stress to the parasite, and addnl. malaria blood stage infection is characterized by intense fever periods. In recent years, it has become clear that heat shock proteins play an essential role during the parasite's life cycle. Plasmodium falciparum expresses two prominent heat shock proteins: heat shock protein 70 (PfHsp70) and heat shock protein 90 (PfHsp90). Both of these proteins have been implicated in the development and pathogenesis of malaria. In eukaryotes, Hsp70 and Hsp90 proteins are functionally linked by an essential adaptor protein known as the Hsp70-Hsp90 organizing protein (Hop). In this study, recombinant P. falciparum Hop (PfHop) was heterologously produced in Escherichia coli and purified by nickel affinity chromatog. Using specific anti-PfHop antisera, the expression and localization of PfHop in P. falciparum was investigated. PfHop was shown to co-localize with PfHsp70 and PfHsp90 in parasites at the trophozoite stage. Gel filtration and co-immunopptn. expts. suggested that PfHop was present in a complex together with PfHsp70 and PfHsp90. The assocn. of PfHop with both PfHsp70 and PfHsp90 suggests that this protein may mediate the functional interaction between the two chaperones.

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29. 29

    Daniyan, M. O., Przyborski, J. M., and Shonhai, A. (2019) Partners in Mischief: Functional Networks of Heat Shock Proteins of Plasmodium Falciparum and Their Influence on Parasite Virulence. Biomolecules 9 (7), 295,  DOI: 10.3390/biom9070295

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    29

    Partners in mischief: functional networks of heat shock proteins of Plasmodium falciparum and their influence on parasite virulence

    Daniyan, Michael O.; Przyborski, Jude M.; Shonhai, Addmore

    Biomolecules (2019), 9 (7), 295CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)

    A review. The survival of the human malaria parasite Plasmodium falciparum under the physiol. distinct environments assocd. with their development in the cold-blooded invertebrate mosquito vectors and the warm-blooded vertebrate human host requires a genome that caters to adaptability. To this end, a robust stress response system coupled to an efficient protein quality control system are essential features of the parasite. Heat shock proteins constitute the main mol. chaperone system of the cell, accounting for approx. two percent of the malaria genome. Some heat shock proteins of parasites constitute a large part (5%) of the %exportome% (parasite proteins that are exported to the infected host erythrocyte) that modify the host cell, promoting its cyto-adherence. In light of their importance in protein folding and refolding, and thus the survival of the parasite, heat shock proteins of P. falciparum have been a major subject of study. Emerging evidence points to their role not only being cyto-protection of the parasite, as they are also implicated in regulating parasite virulence. In undertaking their roles, heat shock proteins operate in networks that involve not only partners of parasite origin, but also potentially functionally assoc. with human proteins to facilitate parasite survival and pathogenicity. This review seeks to highlight these interplays and their roles in parasite pathogenicity. We further discuss the prospects of targeting the parasite heat shock protein network towards the developments of alternative antimalarial chemotherapies.

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30. 30

    Veiga, M. I., Dhingra, S. K., Henrich, P. P., Straimer, J., Gnädig, N., Uhlemann, A. C., Martin, R. E., Lehane, A. M., and Fidock, D. A. (2016) Globally Prevalent PfMDR1Mutations Modulate Plasmodium Falciparum Susceptibility to Artemisinin-Based Combination Therapies. Nat. Commun. 7, 11553,  DOI: 10.1038/ncomms11553

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    30

    Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies

    Veiga, M. Isabel; Dhingra, Satish K.; Henrich, Philipp P.; Straimer, Judith; Gnadig, Nina; Uhlemann, Anne-Catrin; Martin, Rowena E.; Lehane, Adele M.; Fidock, David A.

    Nature Communications (2016), 7 (), 11553CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

    Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated Hb degrdn. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes.

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    Ecker, A., Lehane, A. M., Clain, J., and Fidock, D. A. (2012) PfCRT and Its Role in Antimalarial Drug Resistance. Trends Parasitol. 28 (11), 504– 514,  DOI: 10.1016/j.pt.2012.08.002

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    31

    PfCRT and its role in antimalarial drug resistance

    Ecker, Andrea; Lehane, Adele M.; Clain, Jerome; Fidock, David A.

    Trends in Parasitology (2012), 28 (11), 504-514CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)

    A review. Plasmodium falciparum resistance to chloroquine, the former gold std. antimalarial drug, is mediated primarily by mutant forms of the chloroquine resistance transporter (PfCRT). These mutations impart upon PfCRT the ability to efflux chloroquine from the intracellular digestive vacuole, the site of drug action. Recent studies reveal that PfCRT variants can also affect parasite fitness, protect immature gametocytes against chloroquine action, and alter P. falciparum susceptibility to current first-line therapies. These results highlight the need to be vigilant in screening for the appearance of novel pfcrt alleles that could contribute to new multi-drug resistance phenotypes.

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    Triglia, T., Foote, S. J., Kemp, D. J., and Cowman, A. F. (1991) Amplification of the Multidrug Resistance Gene Pfmdr1 in Plasmodium Falciparum Has Arisen as Multiple Independent Events. Mol. Cell. Biol. 11 (10), 5244– 5250,  DOI: 10.1128/MCB.11.10.5244

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    32

    Amplification of the multidrug resistance gene pfmdr1 in Plasmodium falciparum has arisen as multiple independent events

    Triglia, Tony; Foote, Simon J.; Kemp, David J.; Cowman, Alan F.

    Molecular and Cellular Biology (1991), 11 (10), 5244-50CODEN: MCEBD4; ISSN:0270-7306.

    The multidrug resistance (MDR) phenotype in mammalian tumor cells can involve amplification of mdr genes that results in overexpression of the protein product termed P-glycoprotein. Chloroquine resistance (CQR) in P. falciparum has similarities with the MDR phenotype in tumor cells, and some isolates of P. falciparum have amplified levels of the pfmdr1 gene. To investigate the nature and origin of pfmdr1 amplicons, large regions of a 110-kb amplicon from the CQR cloned isolate B8 were cloned by using the yeast artificial chromosome system. The breakpoints of the amplicon were identified and sequenced by a novel method employing inverted polymerase chain reaction that is applicable to anal. of any large-scale repeat. The 5 copies of the amplicon in this isolate are in a head-to-tail configuration. A string of 30 A's flank the breakpoints on each side of the amplified segment, suggesting a mechanism for the origin of the tandem amplification. Polymerase chain reaction anal. with oligonucleotides that cross the B8 breakpoint has shown in 26 independent CQR isolates, 16 of which contain amplified copies of pfmdr1, that amplification of the pfmdr1 gene in P. falciparum has arisen as multiple independent events. These results suggest that this region of the genome is under strong selective pressure.

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    Le Manach, C., Scheurer, C., Sax, S., Schleiferböck, S., Cabrera, D. G., Younis, Y., Paquet, T., Street, L., Smith, P., Ding, X. C., Waterson, D., Witty, M. J., Leroy, D., Chibale, K., and Wittlin, S. (2013) Fast in Vitro Methods to Determine the Speed of Action and the Stage-Specificity of Anti-Malarials in Plasmodium Falciparum. Malar. J. 12 (1), 424,  DOI: 10.1186/1475-2875-12-424

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    33

    Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum

    Le Manach, Claire; Scheurer, Christian; Sax, Sibylle; Schleiferbock, Sarah; Gonzalez Cabrera, Diego; Younis, Yassir; Paquet, Tanya; Street, Leslie; Smith, Peter; Ding, Xavier C.; Waterson, David; Witty, Michael J.; Leroy, Didier; Chibale, Kelly; Wittlin, Sergio

    Malaria Journal (2013), 12 (), 424/1-424/7, 7 pp.CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)

    Recent whole cell in vitro screening campaigns identified thousands of compds. that are active against asexual blood stages of Plasmodium falciparum at submicromolar concns. These hits were made available to the public, providing many novel chem. starting points for anti-malarial drug discovery programs. Knowing which of these hits are fast-acting compds. is of great interest. Firstly, a fast action will ensure rapid relief of symptoms for the patient. Secondly, by rapidly reducing the parasitemia, this could minimize the occurrence of mutations leading to new drug resistance mechanisms. An in vitro assay that provides information about the speed of action of test compds. was developed by researchers at GlaxoSmithKline (GSK) in Spain. This assay also provides an in vitro measure for the ratio between parasitemia at the onset of drug treatment and after one intra-erythrocytic cycle (parasite redn. ratio, PRR). Both parameters are needed to det. in vitro killing rates of anti-malarial compds. A drawback of the killing rate assay is that it takes a month to obtain 1st results. The approach described in the present study is focused only on the speed of action of anti-malarials. This has the advantage that initial results can be achieved within 4-7 working days, which helps to distinguish between fast and slow-acting compds. relatively quickly. It is expected that this new assay can be used as a filter in the early drug discovery phase, which will reduce the no. of compds. progressing to secondary, more time-consuming assays like the killing rate assay. The speed of action of a selection of 7 anti-malarial compds. was measured with 2 independent exptl. procedures using modifications of the std. [3H]hypoxanthine incorporation assay. Depending on the outcome of both assays, the tested compds. were classified as either fast or non-fast-acting. The results obtained for the anti-malarials chloroquine, artesunate, atovaquone, and pyrimethamine are consistent with previous observations, suggesting the methodol. is a valid way to rapidly identify fast-acting anti-malarial compds. Another advantage of the approach is its ability to discriminate between static or cidal compd. effects.

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    Butterworth, A. S., Skinner-Adams, T. S., Gardiner, D. O. N. L., and Trenholme, K. R. (2013) Plasmodium Falciparum Gametocytes: With a View to a Kill. Parasitology 140 (14), 1718– 1734,  DOI: 10.1017/S0031182013001236

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    34

    Plasmodium falciparum gametocytes: with a view to a kill

    Butterworth, Alice S.; Skinner-Adams, Tina S.; Gardiner, Don L.; Trenholme, Katharine R.

    Parasitology (2013), 140 (14), 1718-1734CODEN: PARAAE; ISSN:0031-1820. (Cambridge University Press)

    A review. Drugs that kill or inhibit the sexual stages of Plasmodium in order to prevent transmission are important components of malaria control programs. Reducing gametocyte carriage is central to the control of Plasmodium falciparum transmission as infection can result in extended periods of gametocytemia. Unfortunately the no. of drugs with activity against gametocytes is limited. Primaquine is currently the only licensed drug with activity against the sexual stages of malaria parasites and its use is hampered by safety concerns. This shortcoming is likely the result of the tech. challenges assocd. with gametocyte studies together with the focus of previous drug discovery campaigns on asexual parasite stages. However recent emphasis on malaria eradication has resulted in an upsurge of interest in identifying compds. with activity against gametocytes. This review examines the gametocytocidal properties of currently available drugs as well as those in the development pipeline and examines the prospects for discovery of new anti-gametocyte compds.

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35. 35

    Capela, R., Magalhães, J., Miranda, D., Machado, M., Sanches-Vaz, M., Albuquerque, I. S., Sharma, M., Gut, J., Rosenthal, P. J., Frade, R., Perry, M. J., Moreira, R., M. Prudêncio, F. L. (2018) Endoperoxide-8-Aminoquinoline Hybrids as Dual-Stage Antimalarial Agents with Enhanced Metabolic Stability. Eur. J. Med. Chem. 149 (149), 69– 78,  DOI: 10.1016/j.ejmech.2018.02.048

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    35

    Endoperoxide-8-aminoquinoline hybrids as dual-stage antimalarial agents with enhanced metabolic stability

    Capela, Rita; Magalhaes, Joana; Miranda, Daniela; Machado, Marta; Sanches-Vaz, Margarida; Albuquerque, Ines S.; Sharma, Moni; Gut, Jiri; Rosenthal, Philip J.; Frade, Raquel; Perry, Maria J.; Moreira, Rui; Prudencio, Miguel; Lopes, Francisca

    European Journal of Medicinal Chemistry (2018), 149 (), 69-78CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

    A library of 1,2,4,5-tetraoxane-8-aminoquinoline hybrids, I [R = Ph, 3-furyl, 4-F3CC6H4, etc.; X = CH(Me), CH2, (CH2)2; Y = CO, CH2] with the metabolically labile C-5 position of the 8-aminoquinoline moiety blocked with aryl groups, was synthesized and screened for antiplasmodial activity and metabolic stability. The hybrid compds. inhibited development of intra-erythrocytic forms of the multidrug-resistant Plasmodium falciparum W2 strain, with EC50 values in the nM range, and with low cytotoxicity against mammalian cells. The compds. also inhibited the development of P. berghei liver stage parasites, with the most potent compds. displaying EC50 values in the low μM range. SAR anal. revealed that unbranched linkers between the endoperoxide and 8-aminoquinoline pharmacophores are most beneficial for dual antiplasmodial activity. Importantly, hybrids were significantly more potent than a 1:1 mixt. of 8-aminoquinoline-tetraoxane, highlighting the superiority of the hybrid approach over the combination therapy. Furthermore, aryl substituents at C-5 of the 8-aminoquinoline moiety improve the compd.'s metabolic stability when compared with their primaquine (i.e. C-5 unsubstituted) counterparts. Overall, this study revealed that blocking the quinoline C-5 position does not resulted in loss of dual-stage antimalarial activity, and that tetraoxane-8-aminoquinoline hybrids were an attractive approach to achieve elimination of exo- and intraerythrocytic parasites, thus with the potential to be used in malaria eradication campaigns.

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36. 36

    Park, E. C., Finley, D., and Szostak, J. W. (1992) A Strategy for the Generation of Conditional Mutations by Protein Destabilization. Proc. Natl. Acad. Sci. U. S. A. 89 (4), 1249– 1252,  DOI: 10.1073/pnas.89.4.1249

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    36

    A strategy for the generation of conditional mutations by protein destabilization

    Park, Eun Chung; Finley, Daniel; Szostak, Jack W.

    Proceedings of the National Academy of Sciences of the United States of America (1992), 89 (4), 1249-52CODEN: PNASA6; ISSN:0027-8424.

    Conditional mutations such as temp.-sensitive (ts) mutations are important for the anal. of protein function but are often difficult, or impossible, to obtain. Here a simple method is presented for generating conditional mutations based on the use of a protein-destabilizing genetic element in combination with systems allowing the induction and repression of gene expression. This genetic cassette can be fused to other protein-coding sequences, and once transcription is turned off and synthesis of the gene product ceases, the preexisting protein is rapidly degraded. This method was applied to the anal. of the yeast ARD1 gene product, a subunit of an N-terminal acetyltransferase, and it is shown that a complete loss of ARD1 product can be achieved in less than one generation. Despite the rapid loss of ARD1 protein, there is a prolonged delay in the expression of the ard1 mutant phenotype, suggesting that the acetylated substrates of ARD1 are metabolically stable and/or exert a long-lasting effect on processes such as the repression of the silent mating type cassettes.

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37. 37

    Parsons, A. B., Brost, R. L., Ding, H., Li, Z., Zhang, C., Sheikh, B., Brown, G. W., Kane, P. M., Hughes, T. R., and Boone, C. (2004) Integration of Chemical-Genetic and Genetic Interaction Data Links Bioactive Compounds to Cellular Target Pathways. Nat. Biotechnol. 22 (1), 62– 69,  DOI: 10.1038/nbt919

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    37

    Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways

    Parsons, Ainslie B.; Brost, Renee L.; Ding, Huiming; Li, Zhijian; Zhang, Chaoying; Sheikh, Bilal; Brown, Grant W.; Kane, Patricia M.; Hughes, Timothy R.; Boone, Charles

    Nature Biotechnology (2004), 22 (1), 62-69CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)

    Bioactive compds. can be valuable research tools and drug leads, but it is often difficult to identify their mechanism of action or cellular target. Here we investigate the potential for integration of chem.-genetic and genetic interaction data to reveal information about the pathways and targets of inhibitory compds. Taking advantage of the existing complete set of yeast haploid deletion mutants, we generated drug-hypersensitivity (chem.-genetic) profiles for 12 compds. In addn. to a set of compd.-specific interactions, the chem.-genetic profiles identified a large group of genes required for multidrug resistance. In particular, yeast mutants lacking a functional vacuolar H+-ATPase show multidrug sensitivity, a phenomenon that may be conserved in mammalian cells. By filtering chem.-genetic profiles for the multidrug-resistant genes and then clustering the compd.-specific profiles with a compendium of large-scale genetic interaction profiles, we were able to identify target pathways or proteins. This method thus provides a powerful means for inferring mechanism of action.

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38. 38

    Giaever, G., Shoemaker, D. D., Jones, T. W., Liang, H., Winzeler, E. A., Astromoff, A., and Davis, R. W. (1999) Genomic Profiling of Drug Sensitivities via Induced Haploinsufficiency. Nat. Genet. 21 (3), 278– 283,  DOI: 10.1038/6791

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    38

    Genomic profiling of drug sensitivities via induced haploinsufficiency

    Giaever, Guri; Shoemaker, Daniel D.; Jones, Ted W.; Liang, Hong; Winzeler, Elizabeth A.; Astromoff, Anna; Davis, Ronald W.

    Nature Genetics (1999), 21 (3), 278-283CODEN: NGENEC; ISSN:1061-4036. (Nature America)

    Lowering the dosage of a single gene from two copies to one copy in diploid yeast results in a heterozygote that is sensitized to any drug that acts on the product of this gene. This haploinsufficient phenotype thereby identifies the gene product of the heterozygous locus as the likely drug target. We exploited this finding in a genomic approach to drug-target identification. Genome sequence information was used to generate molecularly tagged heterozygous yeast strains that were pooled, grown competitively in drug and analyzed for drug sensitivity using high-d. oligonucleotide arrays. Individual heterozygous strain anal. verified six known drug targets. Parallel anal. identified the known target and two hypersensitive loci in a mixed culture of 233 strains in the presence of the drug tunicamycin. Our discovery that both drug target and hypersensitive loci exhibit drug-induced haploinsufficiency may have important consequences in pharmacogenomics and variable drug toxicity obsd. in human populations.

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39. 39

    Smith, A. M., Heisler, L. E., St. Onge, R. P., Farias-Hesson, E., Wallace, I. M., Bodeau, J., Harris, A. N., Perry, K. M., Giaever, G., Pourmand, N., and Nislow, C. (2010) Highly-Multiplexed Barcode Sequencing: An Efficient Method for Parallel Analysis of Pooled Samples. Nucleic Acids Res. 38 (13), e142,  DOI: 10.1093/nar/gkq368

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    39

    Highly-multiplexed barcode sequencing: an efficient method for parallel analysis of pooled samples

    Smith, Andrew M.; Heisler, Lawrence E.; St. Onge, Robert P.; Farias-Hesson, Eveline; Wallace, Iain M.; Bodeau, John; Harris, Adam N.; Perry, Kathleen M.; Giaever, Guri; Pourmand, Nader; Nislow, Corey

    Nucleic Acids Research (2010), 38 (13), e142/1-e142/7CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)

    Next-generation sequencing has proven an extremely effective technol. for mol. counting applications where the no. of sequence reads provides a digital readout for RNA-seq, ChIP-seq, Tn-seq and other applications. The extremely large no. of sequence reads that can be obtained per run permits the anal. of increasingly complex samples. For lower complexity samples, however, a point of diminishing returns is reached when the no. of counts per sequence results in oversampling with no increase in data quality. A soln. to making next-generation sequencing as efficient and affordable as possible involves assaying multiple samples in a single run. Here, we report the successful 96-plexing of complex pools of DNA barcoded yeast mutants and show that such 'Bar-seq' assessment of these samples is comparable with data provided by barcode microarrays, the current benchmark for this application. The cost redn. and increased throughput permitted by highly multiplexed sequencing will greatly expand the scope of chemogenomics assays and, equally importantly, the approach is suitable for other sequence counting applications that could benefit from massive parallelization.

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40. 40

    Hoepfner, 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., and Winzeler, E. A. (2012) Selective and Specific Inhibition of the Plasmodium Falciparum Lysyl-TRNA Synthetase by the Fungal Secondary Metabolite Cladosporin. Cell Host Microbe 11 (6), 654– 663,  DOI: 10.1016/j.chom.2012.04.015

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    40

    Selective and specific inhibition of the Plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin

    Hoepfner, 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.

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41. 41

    Rodger, A., Marrington, R., Roper, D., and Windsor, S. (2005) Circular Dichroism Spectroscopy for the Study of Protein-Ligand Interactions. Methods Mol. Biol. 305, 343– 363,  DOI: 10.1385/1-59259-912-5:343

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    41

    Circular dichroism spectroscopy for the study of protein-ligand interactions

    Rodger, Alison; Marrington, Rachel; Roper, David; Windsor, Stuart

    Methods in Molecular Biology (Totowa, NJ, United States) (2005), 305 (Protein-Ligand Interactions), 343-363CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)

    CD is the difference in absorption of left and right circularly polarized light, usually by a soln. contg. the mols. of interest. A signal is only measured for chiral mols. such as proteins. A CD spectrum provides information about the bonds and structures responsible for this chirality. When a small mol. (or ligand) binds to a protein, it acquires an induced CD (ICD) spectrum through chiral perturbation to its structure or electron rearrangements. The wavelengths of this ICD are detd. by the ligand's own absorption spectrum, and the intensity of the ICD spectrum is detd. by the strength and geometry of its interaction with the protein. Thus, ICD can be used to probe the binding of ligands to proteins. This chapter outlines protein CD and ICD, together with some of the issues relating to exptl. design and implementation.

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    Zsila, F. (2013) Circular Dichroism Spectroscopic Detection of Ligand Binding Induced Subdomain IB Speci Fi c Structural Adjustment of Human Serum Albumin. J. Phys. Chem. B 117 (37), 10798– 10806,  DOI: 10.1021/jp4067108

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    42

    Circular dichroism spectroscopic detection of ligand binding induced subdomain IB specific structural adjustment of human serum albumin

    Zsila, Ferenc

    Journal of Physical Chemistry B (2013), 117 (37), 10798-10806CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    This work demonstrates for the 1st time that binding of various compds. within subdomain IB of human serum albumin (HSA) provokes characteristic changes in the near-UV CD spectrum of the protein. It could be inferred from the spectroscopic features of difference ellipticity signals and from CD displacement expts. that Tyr residues located in subdomain IB were the source of the obsd. spectral alterations. It was proposed that inclusion of some ligand mols. (bile acids, dehydroepiandrosterone sulfate, steroidal terpenes, fatty acids, ibuprofen, and gemfibrozil) into the pocket of subdomain IB disrupted the Tyr-138-Tyr-161 interhelical π-π stacking interaction, which was reflected in the CD spectrum. This phenomenon could be utilized for the CD detection of subdomain IB-specific binding of endogenous as well as exogenous agents and to study the drug binding-assocd. local conformational adaptation of the HSA mol.

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43. 43

    Minari, K., de Azevedo, E. C., Kiraly, V. T. R., Batista, F. A. H., de Moraes, F. R., de Melo, F. A., Nascimento, A. S., Gava, L. M., Ramos, C. H. I., and Borges, J. C. (2019) Thermodynamic Analysis of Interactions of the Hsp90 with Adenosine Nucleotides: A Comparative Perspective. Int. J. Biol. Macromol. 130, 125– 138,  DOI: 10.1016/j.ijbiomac.2019.02.116

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    43

    Thermodynamic analysis of interactions of the Hsp90 with adenosine nucleotides: A comparative perspective

    Minari, Karine; de Azevedo, Erika Chang; Kiraly, Vanessa Thomaz Rodrigues; Batista, Fernanda Aparecida Heleno; de Moraes, Fabio Rogerio; de Melo, Fernando Alves; Nascimento, Alessandro Silva; Gava, Lisandra Marques; Ramos, Carlos Henrique Inacio; Borges, Julio Cesar

    International Journal of Biological Macromolecules (2019), 130 (), 125-138CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)

    Hsp90s are key proteins in cellular homeostasis since they interact with many client proteins. Several studies indicated that Hsp90s are potential targets for treating diseases, such as cancer or malaria. It has been shown that Hsp90s from different organisms have peculiarities despite their high sequence identity. Therefore, a detailed comparative anal. of several Hsp90 proteins is relevant to the overall understanding of their activity. Accordingly, the goal of this work was to evaluate the interaction of either ADP or ATP with recombinant Hsp90s from different organisms (human α and β isoforms, Plasmodium falciparum, Leishmania braziliensis, yeast and sugarcane) by isothermal titrn. calorimetry. The measured thermodn. signatures of those interactions indicated that despite the high identity among all Hsp90s, they have specific thermodn. characteristics. Specifically, the interactions with ADP are driven by enthalpy but are opposed by entropy, whereas the interaction with ATP is driven by both enthalpy and entropy. Complimentary structural and mol. dynamics studies suggested that specific interactions with ADP that differ from those with ATP may contribute to the obsd. enthalpies and entropies. Altogether, the data suggest that selective inhibition may be more easily achieved using analogs of the Hsp90-ADP bound state than those of Hsp90-ATP bound state.

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44. 44

    Silva, K. P., Seraphim, T. V., and Borges, J. C. (2013) Structural and Functional Studies of Leishmania Braziliensis Hsp90. Biochim. Biophys. Acta, Proteins Proteomics 1834 (1), 351– 361,  DOI: 10.1016/j.bbapap.2012.08.004

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    44

    Structural and functional studies of Leishmania braziliensis Hsp90

    Silva, K. P.; Seraphim, T. V.; Borges, J. C.

    Biochimica et Biophysica Acta, Proteins and Proteomics (2013), 1834 (1), 351-361CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B. V.)

    The ubiquitous Hsp90 is crit. for protein homeostasis in the cells, stabilizing 'client' proteins in a functional state. Hsp90 activity depends on its ability to bind and hydrolyze ATP, involving various conformational changes that are regulated by co-chaperones, posttranslational modifications and small mols. Compds. like geldanamycin (GA) and radicicol inhibit the Hsp90 ATPase activity by occupying the ATP binding site, which can lead client protein to degrdn. and also inhibit cell growth and differentiation in protozoan parasites. Our goal was to produce the recombinant Hsp90 of Leishmania braziliensis (LbHsp90) and construct of its N-terminal (LbHsp90N) and N-domain and middle-domain (LbHsp90NM), which lacks the C-terminal dimerization domain, in order to understand how Hsp90 works in protozoa. The recombinant proteins were produced folded as attested by spectroscopy expts. Hydrodynamic expts. revealed that LbHsp90N and LbHsp90NM behaved as elongated monomers while LbHsp90 is an elongated dimer. All proteins prevented the in vitro citrate synthase and malate dehydrogenase aggregation, attesting that they have chaperone activity, and interacted with adenosine ligands with similar dissocn. consts. The LbHsp90 has low ATPase activity (kcat = 0.320 min-1) in agreement with Hsp90 orthologs, whereas the LbHsp90NM has negligible activity, suggesting the importance of the dimeric protein for this activity. The GA interacts with LbHsp90 and with its domain constructions with different affinities and also inhibits the LbHsp90 ATPase activity with an IC50 of 0.7 μM. All these results shed light on the LbHsp90 activity and are the first step to understanding the Hsp90 mol. chaperone system in L. braziliensis.

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45. 45

    Montgomery, D. L., Morimoto, R. I., and Gierasch, L. M. (1999) Mutations in the Substrate Binding Domain of the Escherichia Coli 70 KDa Molecular Chaperone, DnaK, Which Alter Substrate Affinity or Interdomain Coupling. J. Mol. Biol. 286 (3), 915– 932,  DOI: 10.1006/jmbi.1998.2514

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    45

    Mutations in the Substrate Binding Domain of the Escherichia coli 70 kDa Molecular Chaperone, DnaK, which Alter Substrate Affinity or Interdomain Coupling

    Montgomery, Diana L.; Morimoto, Richard I.; Gierasch, Lila M.

    Journal of Molecular Biology (1999), 286 (3), 915-932CODEN: JMOBAK; ISSN:0022-2836. (Academic Press)

    In Escherichia coli, DnaK is essential for the replication of bacteriophage λ DNA; this in vivo activity provides the basis of a screen for mutations affecting DnaK function. Mn PCR was used to introduce mutations into residues 405-468 of the C-terminal polypeptide-binding domain of DnaK. These mutant proteins were screened for the ability to propagate bacteriophage λ in the background of dnaK deficient cell line, BB1553. This initial screen identified several proteins which were mutant at multiple positions. The multiple mutants were further dissected into single mutants which remained neg. for λ propagation. Four of these single-site mutants were purified and assayed for biochem. functionality. Two single-site mutations, F426S and S427P, are localized in the peptide binding site and display weakened peptide binding affinity. This indicates that the crystallog. detd. peptide binding site is also crit. for in vivo λ replication. Two other mutations, K414I and N451K, are located at the edge of the β-sandwich domain near α-helix A. The K414I mutant binds peptide moderately well, yet displays defects in allosteric functions, including peptide-stimulated ATPase activity, ATP-induced changes in tryptophan fluorescence, ATP-induced peptide release, and elevated ATPase activity. The K414 position is close in tertiary structure to the linker region to the ATPase domain and reflects a specific area of the peptide-binding domain which is necessary for interdomain coupling. The mutant N451K displays defects in both peptide binding and allosteric interaction. (c) 1999 Academic Press.

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46. 46

    Batinovic, S., McHugh, E., Chisholm, S. A., Matthews, K., Liu, B., Dumont, L., Charnaud, S. C., Schneider, M. P., Gilson, P. R., De Koning-Ward, T. F., Dixon, M. W. A., and Tilley, L. (2017) An Exported Protein-Interacting Complex Involved in the Trafficking of Virulence Determinants in Plasmodium-Infected Erythrocytes. Nat. Commun. 8 (1), 16044,  DOI: 10.1038/ncomms16044

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    46

    An exported protein-interacting complex involved in the trafficking of virulence determinants in Plasmodium-infected erythrocytes

    Batinovic, Steven; McHugh, Emma; Chisholm, Scott A.; Matthews, Kathryn; Liu, Boiyin; Dumont, Laure; Charnaud, Sarah C.; Schneider, Molly Parkyn; Gilson, Paul R.; de Koning-Ward, Tania F.; Dixon, Matthew W. A.; Tilley, Leann

    Nature Communications (2017), 8 (), 16044CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

    The malaria parasite, Plasmodium falciparum, displays the P. falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface of infected red blood cells (RBCs). We here examine the phys. organization of PfEMP1 trafficking intermediates in infected RBCs and det. interacting partners using an epitope-tagged minimal construct (PfEMP1B). We show that parasitophorous vacuole (PV)-located PfEMP1B interacts with components of the PTEX (Plasmodium Translocon of EXported proteins) as well as a novel protein complex, EPIC (Exported Protein-Interacting Complex). Within the RBC cytoplasm PfEMP1B interacts with components of the Maurer's clefts and the RBC chaperonin complex. We define the EPIC interactome and, using an inducible knockdown approach, show that depletion of one of its components, the parasitophorous vacuolar protein-1 (PV1), results in altered knob morphol., reduced cell rigidity and decreased binding to CD36. Accordingly, we show that deletion of the Plasmodium berghei homolog of PV1 is assocd. with attenuation of parasite virulence in vivo.

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47. 47

    Roe, S. M., Prodromou, C., O'Brien, R., Ladbury, J. E., Piper, P. W., and Pearl, L. H. (1999) Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin. J. Med. Chem. 42 (2), 260– 266,  DOI: 10.1021/jm980403y

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    47

    Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin

    Roe, S. Mark; Prodromou, Chrisostomos; O'Brien, Ronan; Ladbury, John E.; Piper, Peter W.; Pearl, Laurence H.

    Journal of Medicinal Chemistry (1999), 42 (2), 260-266CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The cellular activity of several regulatory and signal transduction proteins, which depend on the Hsp90 mol. chaperone for folding, is markedly decreased by geldanamycin and by radicicol (monorden). We now show that these unrelated compds. both bind to the N-terminal ATP/ADP-binding domain of Hsp90, with radicicol displaying nanomolar affinity, and both inhibit the inherent ATPase activity of Hsp90 which is essential for its function in vivo. Crystal structure detns. of Hsp90 N-terminal domain complexes with geldanamycin and radicicol identify key aspects of their nucleotide mimicry and suggest a rational basis for the design of novel antichaperone drugs.

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48. 48

    Stebbins, C. E., Russo, A. A., Schneider, C., Rosen, N., Hartl, F. U., and Pavletich, N. P. (1997) Crystal Structure of an Hsp90 - Geldanamycin Complex: Targeting of a Protein Chaperone by an Antitumor Agent. Cell 89 (2), 239– 250,  DOI: 10.1016/S0092-8674(00)80203-2

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    48

    Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent

    Stebbins, Charles E.; Russo, Alicia A.; Schneider, Christine; Rosen, Neal; Hartl, F. Ulrich; Pavletich, Nikola P.

    Cell (Cambridge, Massachusetts) (1997), 89 (2), 239-250CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    The Hsp90 chaperone is required for the activation of several families of eukaryotic protein kinases and nuclear hormone receptors, many of which are proto-oncogenic and play a prominent role in cancer. The geldanamycin antibiotic has antiproliferative and anti-tumor effects, as it binds to Hsp90, inhibits the Hsp90-mediated conformational maturation/refolding reaction, and results in the degrdn. of Hsp90 substrates. The structure of the geldanamycin-binding domain of Hsp90 (residues 9-232) reveals a pronounced pocket, 15 Å deep. that is highly conserved across species. Geldanamycin binds inside this pocket, adopting a compact structure similar to that of a polypeptide chain in a turn conformation. This, and the pocket's similarity to substrate-binding sites, suggest that the pocket binds a portion of the polypeptide substrate and participates in the conformational maturation/refolding reaction.

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    Whitesell, L., Mimnaugh, E. G., De Costa, B., Myers, C. E., and Neckers, L. M. (1994) Inhibition of Heat Shock Protein HSP90-Pp6Ov-Src Heteroprotein Complex Formation by Benzoquinone Ansamycins: Essential Role for Stress Proteins in Oncogenic Transformation. Proc. Natl. Acad. Sci. U. S. A. 91 (18), 8324– 8328,  DOI: 10.1073/pnas.91.18.8324

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    49

    Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation

    Whitesell, Luke; Mimnaugh, Edward G.; De Costa, Brian; Myers, Charles E.; Neckers, Leonard M.

    Proceedings of the National Academy of Sciences of the United States of America (1994), 91 (18), 8324-8CODEN: PNASA6; ISSN:0027-8424.

    The mol. mechanisms by which oncogenic tyrosine kinases induce cellular transformation are unclear. Herbimycin A, geldanamycin, and certain other benzoquinone ansamycins display an unusual capacity to revert tyrosine kinase-induced oncogenic transformation. As an approach to the study of v-src-mediated transformation, the authors examd. ansamycin action in transformed cells and found that drug-induced reversion could be achieved without direct inhibition of src phosphorylating activity. To identify mechanisms other than kinase inhibition for drug-mediated reversion, the authors prepd. a solid phase-immobilized geldanamycin deriv. and affinity pptd. the mol. targets with which the drug interacted. In a range of cell lines, immobilized geldanamycin bound elements of a major class of heat shock protein (HSP90) in a stable and pharmacol. specific manner. Consistent with these binding data, the authors found that sol. geldanamycin and herbimycin A inhibited specifically the formation of a previously described src-HSP90 heteroprotein complex. A related benzoquinone ansamycin that failed to revert transformed cells did not inhibit the formation of this complex. These results demonstrate that HSP participation in multimol. complex formation is required for src-mediated transformation and can provide a target for drug modulation.

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    Li, J., Soroka, J., and Buchner, J. (2012) The Hsp90 Chaperone Machinery: Conformational Dynamics and Regulation by Co-Chaperones. Biochim. Biophys. Acta, Mol. Cell Res. 1823, 624– 635,  DOI: 10.1016/j.bbamcr.2011.09.003

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    50

    The Hsp90 chaperone machinery: Conformational dynamics and regulation by co-chaperones

    Li, Jing; Soroka, Joanna; Buchner, Johannes

    Biochimica et Biophysica Acta, Molecular Cell Research (2012), 1823 (3), 624-635CODEN: BBAMCO; ISSN:0167-4889. (Elsevier B.V.)

    Hsp90 is a dimeric mol. chaperone required for the activation and stabilization of numerous client proteins many of which are involved in essential cellular processes like signal transduction pathways. This activation process is regulated by ATP-induced large conformational changes, co-chaperones and posttranslational modifications. For some co-chaperones, a detailed picture on their structures and functions exists, for others their contributions to the Hsp90 system is still unclear. Recent progress on the conformational dynamics of Hsp90 and how co-chaperones affect the Hsp90 chaperone cycle significantly increased our understanding of the gearings of this complex mol. machinery.

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    Silva, K. P. and Borges, J. C. (2011) The Molecular Chaperone Hsp70 Family Members Function by a Bidirec- Tional Heterotrophic Allosteric Mechanism. Protein Pept. Lett. 18 (2), 132– 142,  DOI: 10.2174/092986611794475057

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52. 52

    Young, J. C. (2010) Mechanisms of the Hsp70 Chaperone System. Biochem. Cell Biol. 88 (2), 291– 300,  DOI: 10.1139/O09-175

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    52

    Mechanisms of the Hsp70 chaperone system

    Young, Jason C.

    Biochemistry and Cell Biology (2010), 88 (2), 291-300CODEN: BCBIEQ; ISSN:0829-8211. (National Research Council of Canada)

    A review. Mol. chaperones of the Hsp70 family have diverse functions in cells. They assist the folding of newly synthesized and stress-denatured proteins, as well as the import of proteins into organelles, and the dissocn. of aggregated proteins. The well-conserved Hsp70 chaperones are ATP-dependent. Binding and hydrolysis of ATP regulates their interactions with unfolded polypeptide substrates, and ATPase cycling is necessary for their function. All cellular functions of Hsp70 chaperones use the same mechanism of ATP-driven polypeptide binding and release. The Hsp40 co-chaperones stimulate ATP hydrolysis by Hsp70 and the type 1 Hsp40 proteins are conserved from Escherichia coli to humans. Various nucleotide exchange factors also promote the Hsp70 ATPase cycle. Recent advances have added to the understanding of the Hsp70 mechanism at a mol. level.

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    Clerico, E. M., Tilitsky, J. M., Meng, W., and Gierasch, L. M. (2015) How Hsp70 Molecular Machines Interact with Their Substrates to Mediate Diverse Physiological Functions. J. Mol. Biol. 427 (7), 1575– 1588,  DOI: 10.1016/j.jmb.2015.02.004

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    53

    How Hsp70 molecular machines interact with their substrates to mediate diverse physiological functions

    Clerico, Eugenia M.; Tilitsky, Joseph M.; Meng, Wenli; Gierasch, Lila M.

    Journal of Molecular Biology (2015), 427 (7), 1575-1588CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)

    A review. Hsp70 mol. chaperones are implicated in a wide variety of cellular processes, including protein biogenesis, protection of the proteome from stress, recovery of proteins from aggregates, facilitation of protein translocation across membranes, and more specialized roles such as disassembly of particular protein complexes. It is a fascinating question to ask how the mechanism of these deceptively simple mol. machines is matched to their roles in these wide-ranging processes. The key is a combination of the nature of the recognition and binding of Hsp70 substrates and the impact of Hsp70 action on their substrates. In many cases, the binding, which relies on interaction with an extended, accessible short hydrophobic sequence, favors more unfolded states of client proteins. The ATP-mediated dissocn. of the substrate thus releases it in a relatively less folded state for downstream folding, membrane translocation, or hand-off to another chaperone. There are cases, such as regulation of the heat shock response or disassembly of clathrin coats, however, where binding of a short hydrophobic sequence selects conformational states of clients to favor their productive participation in a subsequent step. Here, the authors discuss the current understanding of how Hsp70 mol. chaperones recognize and act on their substrates and the relations between these fundamental processes and the functional roles played by these mol. machines.

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    Kityk, R., Kopp, J., Sinning, I., and Mayer, M. P. (2012) Structure and Dynamics of the ATP-Bound Open Conformation of Hsp70 Chaperones. Mol. Cell 48 (6), 863– 874,  DOI: 10.1016/j.molcel.2012.09.023

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    54

    Structure and Dynamics of the ATP-Bound Open Conformation of Hsp70 Chaperones

    Kityk, Roman; Kopp, Juergen; Sinning, Irmgard; Mayer, Matthias P.

    Molecular Cell (2012), 48 (6), 863-874CODEN: MOCEFL; ISSN:1097-2765. (Elsevier Inc.)

    Central to the chaperone function of Hsp70s is the transition between open and closed conformations of their polypeptide substrate binding domain (SBD), which is regulated through an allosteric mechanism via ATP binding and hydrolysis in their nucleotide binding domain (NBD). Although the structure of the closed conformation of Hsp70s is well studied, the open conformation has remained elusive. Here, we report on the 2.4 Å crystal structure of the ATP-bound open conformation of the Escherichia coli Hsp70 homolog DnaK. In the open DnaK structure, the β sheet and α-helical lid subdomains of the SBD are detached from one another and docked to different faces of the NBD. The contacts between the β sheet subdomain and the NBD reveal the mechanism of allosteric regulation. In addn., we demonstrate that docking of the β sheet and α-helical lid subdomains to the NBD is a sequential process influenced by peptide and protein substrates.

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    Liberek, K., Lewandowska, A., and Zietkiewicz, S. (2008) Chaperones in Control of Protein Disaggregation. EMBO J. 27 (2), 328– 335,  DOI: 10.1038/sj.emboj.7601970

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    55

    Chaperones in control of protein disaggregation

    Liberek, Krzysztof; Lewandowska, Agnieszka; Zietkiewicz, Szymon

    EMBO Journal (2008), 27 (2), 328-335CODEN: EMJODG; ISSN:0261-4189. (Nature Publishing Group)

    The chaperone protein network controls both initial protein folding and subsequent maintenance of proteins in the cell. Although the native structure of a protein is principally encoded in its amino-acid sequence, the process of folding in vivo very often requires the assistance of mol. chaperones. Chaperones also play a role in a post-translational quality control system and thus are required to maintain the proper conformation of proteins under changing environmental conditions. Many factors leading to unfolding and misfolding of proteins eventually result in protein aggregation. Stress imposed by high temp. was one of the first aggregation-inducing factors studied and remains one of the main models in this field. With massive protein aggregation occurring in response to heat exposure, the cell needs chaperones to control and counteract the aggregation process. Elimination of aggregates can be achieved by solubilization of aggregates and either refolding of the liberated polypeptides or their proteolysis. Here, we focus on the mol. mechanisms by which heat-shock protein 70 (Hsp70), Hsp100 and small Hsp chaperones liberate and refold polypeptides trapped in protein aggregates.

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    Silva, K. P., Seraphim, T. V., and Borges, J. C. (2013) Structural and Functional Studies of Leishmania Braziliensis Hsp90. Biochim. Biophys. Acta, Proteins Proteomics 1834 (1), 351– 361,  DOI: 10.1016/j.bbapap.2012.08.004

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    56

    Structural and functional studies of Leishmania braziliensis Hsp90

    Silva, K. P.; Seraphim, T. V.; Borges, J. C.

    Biochimica et Biophysica Acta, Proteins and Proteomics (2013), 1834 (1), 351-361CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B. V.)

    The ubiquitous Hsp90 is crit. for protein homeostasis in the cells, stabilizing 'client' proteins in a functional state. Hsp90 activity depends on its ability to bind and hydrolyze ATP, involving various conformational changes that are regulated by co-chaperones, posttranslational modifications and small mols. Compds. like geldanamycin (GA) and radicicol inhibit the Hsp90 ATPase activity by occupying the ATP binding site, which can lead client protein to degrdn. and also inhibit cell growth and differentiation in protozoan parasites. Our goal was to produce the recombinant Hsp90 of Leishmania braziliensis (LbHsp90) and construct of its N-terminal (LbHsp90N) and N-domain and middle-domain (LbHsp90NM), which lacks the C-terminal dimerization domain, in order to understand how Hsp90 works in protozoa. The recombinant proteins were produced folded as attested by spectroscopy expts. Hydrodynamic expts. revealed that LbHsp90N and LbHsp90NM behaved as elongated monomers while LbHsp90 is an elongated dimer. All proteins prevented the in vitro citrate synthase and malate dehydrogenase aggregation, attesting that they have chaperone activity, and interacted with adenosine ligands with similar dissocn. consts. The LbHsp90 has low ATPase activity (kcat = 0.320 min-1) in agreement with Hsp90 orthologs, whereas the LbHsp90NM has negligible activity, suggesting the importance of the dimeric protein for this activity. The GA interacts with LbHsp90 and with its domain constructions with different affinities and also inhibits the LbHsp90 ATPase activity with an IC50 of 0.7 μM. All these results shed light on the LbHsp90 activity and are the first step to understanding the Hsp90 mol. chaperone system in L. braziliensis.

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    Kravats, A. N., Hoskins, J. R., Reidy, M., Johnson, J. L., Doyle, S. M., Genest, O., Masison, D. C., and Wickner, S. (2018) Functional and Physical Interaction between Yeast Hsp90 and Hsp70. Proc. Natl. Acad. Sci. U. S. A. 115 (10), E2210– E2219,  DOI: 10.1073/pnas.1719969115

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    57

    Functional and physical interaction between yeast Hsp90 and Hsp70

    Kravats, Andrea N.; Hoskins, Joel R.; Reidy, Michael; Johnson, Jill L.; Doyle, Shannon M.; Genest, Olivier; Masison, Daniel C.; Wickner, Sue

    Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (10), E2210-E2219CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    Heat shock protein 90 (Hsp90) is a highly conserved ATP-dependent mol. chaperone that is essential in eukaryotes. It is required for the activation and stabilization of more than 200 client proteins, including many kinases and steroid hormone receptors involved in cell-signaling pathways. Hsp90 chaperone activity requires collaboration with a subset of the many Hsp90 cochaperones, including the Hsp70 chaperone. In higher eukaryotes, the collaboration between Hsp90 and Hsp70 is indirect and involves Hop, a cochaperone that interacts with both Hsp90 and Hsp70. Here we show that yeast Hsp90 (Hsp82) and yeast Hsp70 (Ssa1), directly interact in vitro in the absence of the yeast Hop homolog (Sti1), and identify a region in the middle domain of yeast Hsp90 that is required for the interaction. In vivo results using Hsp90 substitution mutants showed that several residues in this region were important or essential for growth at high temp. Moreover, mutants in this region were defective in interaction with Hsp70 in cell lysates. In vitro, the purified Hsp82 mutant proteins were defective in direct phys. interaction with Ssa1 and in protein remodeling in collaboration with Ssa1 and cochaperones. This region of Hsp90 is also important for interactions with several Hsp90 cochaperones and client proteins, suggesting that collaboration between Hsp70 and Hsp90 in protein remodeling may be modulated through competition between Hsp70 and Hsp90 cochaperones for the interaction surface.

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    Leu, J. I., Pimkina, J., Pandey, P., Murphy, M. E., and George, D. L. (2011) HSP70 Inhibition by the Small-Molecule 2-Phenylethynesulfonamide Impairs Protein Clearance Pathways in Tumor Cells. Mol. Cancer Res. 9 (7), 936– 948,  DOI: 10.1158/1541-7786.MCR-11-0019

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    58

    HSP70 Inhibition by the Small-Molecule 2-Phenylethynesulfonamide Impairs Protein Clearance Pathways in Tumor Cells

    Leu, J. I.-Ju; Pimkina, Julia; Pandey, Pooja; Murphy, Maureen E.; George, Donna L.

    Molecular Cancer Research (2011), 9 (7), 936-947CODEN: MCROC5; ISSN:1541-7786. (American Association for Cancer Research)

    The evolutionarily conserved stress-inducible HSP70 mol. chaperone plays a central role in maintaining protein quality control in response to various forms of stress. Constitutively elevated HSP70 expression is a characteristic of many tumor cells and contributes to their survival. We recently identified the small-mol. 2-phenylethyenesulfonamide (PES) as a novel HSP70 inhibitor. Here, we present evidence that PES-mediated inhibition of HSP70 family proteins in tumor cells results in an impairment of the two major protein degrdn. systems, namely, the autophagy-lysosome system and the proteasome pathway. HSP70 family proteins work closely with the HSP90 mol. chaperone to maintain the stability and activities of their many client proteins, and PES causes a disruption in the HSP70/HSP90 chaperone system. As a consequence, many cellular proteins, including known HSP70/HSP90 substrates, accumulate in detergent-insol. cell fractions, indicative of aggregation and functional inactivation. Overall, PES simultaneously disrupts several cancer crit. survival pathways, supporting the idea of targeting HSP70 as a potential approach for cancer therapeutics. Mol Cancer Res; 9(7); 936-47.

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    Leu, J. I-J., Pimkina, J., Frank, A., Murphy, M. E., and George, D. L. (2009) A Small Molecule Inhibitor of Inducible Heat Shock Protein 70 (HSP70). Mol. Cell 36 (1), 15– 27,  DOI: 10.1016/j.molcel.2009.09.023

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    59

    A small molecule inhibitor of inducible heat shock protein 70

    Leu, J. I.-Ju; Pimkina, Julia; Frank, Amanda; Murphy, Maureen E.; George, Donna L.

    Molecular Cell (2009), 36 (1), 15-27CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)

    The multifunctional, stress-inducible mol. chaperone HSP70 has important roles in aiding protein folding and maintaining protein homeostasis. HSP70 expression is elevated in many cancers, contributing to tumor cell survival and resistance to therapy. We have detd. that a small mol. called 2-phenylethynesulfonamide (PES) interacts selectively with HSP70 and leads to a disruption of the assocn. between HSP70 and several of its co-chaperones and substrate proteins. Treatment of cultured tumor cells with PES promotes cell death that is assocd. with protein aggregation, impaired autophagy, and inhibition of lysosomal function. Moreover, this small mol. is able to suppress tumor development and enhance survival in a mouse model of Myc-induced lymphomagenesis. The data demonstrate that PES disrupts actions of HSP70 in multiple cell signaling pathways, offering an opportunity to better understand the diverse functions of this mol. chaperone and also to aid in the development of new cancer therapies.

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    Galluzzi, L., Diotallevi, A., and Magnani, M. (2017) Endoplasmic Reticulum Stress and Unfolded Protein Response in Infection by Intracellular Parasites. Futur. Sci. OA 3 (3), FSO198,  DOI: 10.4155/fsoa-2017-0020

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61. 61

    Bridgford, J. L., Xie, S. C., Cobbold, S. A., Pasaje, C. F. A., Herrmann, S., Yang, T., Gillett, D. L., Dick, L. R., Ralph, S. A., Spillman, N. J., Tilley, L., and Dogovski, C. (2018) Artemisinin Kills Malaria Parasites by Damaging Proteins and Inhibiting the Proteasome. Nat. Commun. 9, 3801,  DOI: 10.1038/s41467-018-06221-1

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    61

    Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome

    Bridgford Jessica L; Xie Stanley C; Cobbold Simon A; Pasaje Charisse Flerida A; Herrmann Susann; Yang Tuo; Gillett David L; Ralph Stuart A; Dogovski Con; Spillman Natalie J; Tilley Leann; Dick Lawrence R

    Nature communications (2018), 9 (1), 3801 ISSN:.

    Artemisinin and its derivatives (collectively referred to as ARTs) rapidly reduce the parasite burden in Plasmodium falciparum infections, and antimalarial control is highly dependent on ART combination therapies (ACTs). Decreased sensitivity to ARTs is emerging, making it critically important to understand the mechanism of action of ARTs. Here we demonstrate that dihydroartemisinin (DHA), the clinically relevant ART, kills parasites via a two-pronged mechanism, causing protein damage, and compromising parasite proteasome function. The consequent accumulation of proteasome substrates, i.e., unfolded/damaged and polyubiquitinated proteins, activates the ER stress response and underpins DHA-mediated killing. Specific inhibitors of the proteasome cause a similar build-up of polyubiquitinated proteins, leading to parasite killing. Blocking protein synthesis with a translation inhibitor or inhibiting the ubiquitin-activating enzyme, E1, reduces the level of damaged, polyubiquitinated proteins, alleviates the stress response, and dramatically antagonizes DHA activity.

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62. 62

    Xie, S. C., Gillett, D. L., Spillman, N. J., Tsu, C., Luth, M. R., Ottilie, S., Duffy, S., Gould, A. E., Hales, P., Seager, B. A., Charron, C. L., Bruzzese, F., Yang, X., Zhao, X., Huang, S.-C., Hutton, C. A., Burrows, J. N., Winzeler, E. A., Avery, V. M., Dick, L. R., and Tilley, L. (2018) Target Validation and Identi Fi Cation of Novel Boronate Inhibitors of the Plasmodium Falciparum Proteasome. J. Med. Chem. 61 (22), 10053– 10066,  DOI: 10.1021/acs.jmedchem.8b01161

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    62

    Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome

    Xie, Stanley C.; Gillett, David L.; Spillman, Natalie J.; Tsu, Christopher; Luth, Madeline R.; Ottilie, Sabine; Duffy, Sandra; Gould, Alexandra E.; Hales, Paul; Seager, Benjamin A.; Charron, Carlie L.; Bruzzese, Frank; Yang, Xiaofeng; Zhao, Xiansi; Huang, Shih-Chung; Hutton, Craig A.; Burrows, Jeremy N.; Winzeler, Elizabeth A.; Avery, Vicky M.; Dick, Lawrence R.; Tilley, Leann

    Journal of Medicinal Chemistry (2018), 61 (22), 10053-10066CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The Plasmodium proteasome represents a potential antimalarial drug target for compds. with activity against multiple life cycle stages. The authors screened a library of human proteasome inhibitors (peptidyl boronic acids) and compared activities against purified P. falciparum and human 20S proteasomes. The authors chose four hits that potently inhibit parasite growth and show a range of selectivities for inhibition of the growth of P. falciparum compared with human cell lines. P. falciparum was selected for resistance in vitro to the clin. used proteasome inhibitor, bortezomib, and whole genome sequencing was applied to identify mutations in the proteasome β5 subunit. Active site profiling revealed inhibitor features that enable retention of potent activity against the bortezomib-resistant line. Substrate profiling reveals P. falciparum 20S proteasome active site preferences that will inform attempts to design more selective inhibitors. This work provides a starting point for the identification of antimalarial drug leads that selectively target the P. falciparum proteasome.

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    Buchberger, A., Bukau, B., and Sommer, T. (2010) Protein Quality Control in the Cytosol and the Endoplasmic Reticulum: Brothers in Arms. Mol. Cell 40 (2), 238– 252,  DOI: 10.1016/j.molcel.2010.10.001

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    63

    Protein quality control in the cytosol and the endoplasmic reticulum: Brothers in arms

    Buchberger, Alexander; Bukau, Bernd; Sommer, Thomas

    Molecular Cell (2010), 40 (2), 238-252CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)

    A review. In cells, both newly synthesized and pre-existing proteins are constantly endangered by misfolding and aggregation. The accumulation of damaged proteins can perturb cellular homeostasis and provoke aging, pathol. states, and even cell death. To avert these dangers, cells have developed powerful quality control (QC) strategies that counteract protein damage in a compartment-specific way. Here, the authors compare the protein QC systems of the eukaryotic cytosol and the endoplasmic reticulum, focusing on the principles of damage recognition, the triage decisions between chaperone-mediated refolding and proteolytic elimination of damaged proteins, the repair of misfolded and aggregated protein species, and the mechanisms by which perturbations of protein homeostasis are sensed to induce compartment-specific stress responses.

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    Antonova-Koch, Y., Meister, S., Abraham, M., Luth, M. R., Ottilie, S., Lukens, A. K., Sakata-Kato, T., Vanaerschot, M., Owen, E., Jado Rodriguez, 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. L., 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., and Winzeler, E. A. (2018) Open-Source Discovery of Chemical Leads for next-Generation Chemoprotective Antimalarials. Science 362 (6419), eaat9446,  DOI: 10.1126/science.aat9446

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    Bermúdez, M., Andrés, D., Pérez, M., Pinzón, G. A., Curtidor, H., and Patarroyo, M. A. (2018) Plasmodium Vivax in Vitro Continuous Culture: The Spoke in the Wheel. Malar. J. 1– 12,  DOI: 10.1186/s12936-018-2456-5

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    Bousema, T. and Drakeley, C. (2011) Epidemiology and Infectivity of Plasmodium Falciparum and Plasmodium Vivax Gametocytes in Relation to Malaria Control and Elimination. Clin. Microbiol. Rev. 24 (2), 377– 410,  DOI: 10.1128/CMR.00051-10

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    66

    Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination

    Bousema Teun; Drakeley Chris

    Clinical microbiology reviews (2011), 24 (2), 377-410 ISSN:.

    Malaria remains a major cause of morbidity and mortality in the tropics, with Plasmodium falciparum responsible for the majority of the disease burden and P. vivax being the geographically most widely distributed cause of malaria. Gametocytes are the sexual-stage parasites that infect Anopheles mosquitoes and mediate the onward transmission of the disease. Gametocytes are poorly studied despite this crucial role, but with a recent resurgence of interest in malaria elimination, the study of gametocytes is in vogue. This review highlights the current state of knowledge with regard to the development and longevity of P. falciparum and P. vivax gametocytes in the human host and the factors influencing their distribution within endemic populations. The evidence for immune responses, antimalarial drugs, and drug resistance influencing infectiousness to mosquitoes is reviewed. We discuss how the application of molecular techniques has led to the identification of submicroscopic gametocyte carriage and to a reassessment of the human infectious reservoir. These components are drawn together to show how control measures that aim to reduce malaria transmission, such as mass drug administration and a transmission-blocking vaccine, might better be deployed.

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    Moran Luengo, T., Mayer, M. P., and Rudiger, S. G.D. (2019) The Hsp70 - Hsp90 Chaperone Cascade in Protein Folding. Trends Cell Biol. 29 (2), 164– 177,  DOI: 10.1016/j.tcb.2018.10.004

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    69

    The Hsp70-Hsp90 Chaperone Cascade in Protein Folding

    Moran Luengo, Tania; Mayer, Matthias P.; Ruediger, Stefan G. D.

    Trends in Cell Biology (2019), 29 (2), 164-177CODEN: TCBIEK; ISSN:0962-8924. (Elsevier Ltd.)

    A review. Conserved families of mol. chaperones assist protein folding in the cell. Here we review the conceptual advances on three major folding routes: (i) spontaneous, chaperone-independent folding; (ii) folding assisted by repetitive Hsp70 cycles; and (iii) folding by the Hsp70-Hsp90 cascades. These chaperones prep. their protein clients for folding on their own, without altering their folding path. A particularly interesting role is reserved for Hsp90. The function of Hsp90 in folding is its ancient function downstream of Hsp70, free of cochaperone regulation and present in all kingdoms of life. Eukaryotic signalling networks, however, embrace Hsp90 by a plethora of cochaperones, transforming the profolding machinery to a folding-on-demand factor. We discuss implications for biol. and mol. medicine.

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68. 68

    Wilkinson, M. D., Lai, H.-E., Freemont, P. S., and Baum, J. (2020) A Biosynthetic Platform for Antimalarial Drug Discovery. Antimicrob. Agents Chemother.  DOI: 10.1128/AAC.02129-19

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69. 69

    Neckers, L. and Workman, P. (2012) Hsp90 Molecular Chaperone Inhibitors: Are We There Yet?. Clin. Cancer Res. 18 (1), 64– 76,  DOI: 10.1158/1078-0432.CCR-11-1000

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    71

    Hsp90 Molecular Chaperone Inhibitors: Are We There Yet?

    Neckers, Len; Workman, Paul

    Clinical Cancer Research (2012), 18 (1), 64-76CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)

    A review. Heat shock protein (Hsp) 90 is an ATP-dependent mol. chaperone that is exploited by malignant cells to support activated oncoproteins, including many cancer-assocd. kinases and transcription factors, and it is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now being actively pursued by the pharmaceutical industry, with 17 agents having entered clin. trials. Investigators established Hsp90's druggability using the natural products geldanamycin and radicicol, which mimic the unusual ATP structure adopted in the chaperone's N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis, inhibit chaperone function, deplete oncogenic clients, and show antitumor activity. Preclin. data obtained with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has shown clin. activity (as defined by Response Evaluation Criteria in Solid Tumors) in HER2+ breast cancer. Many optimized synthetic, small-mol. Hsp90 inhibitors from diverse chemotypes are now in clin. trials. Here, we review the discovery and development of Hsp90 inhibitors and assess their potential. There has been significant learning from studies of the basic biol. of Hsp90, as well as translational drug development involving this chaperone, enhanced by the use of Hsp90 inhibitors as chem. probes. Success will likely lie in treating cancers that are addicted to particular driver oncogene products (e.g., HER2, ALK, EGFR, and BRAF) that are sensitive Hsp90 clients, as well as malignancies (esp. multiple myeloma) in which buffering of proteotoxic stress is crit. for survival. We discuss approaches for enhancing the effectiveness of Hsp90 inhibitors and highlight new chaperone and stress-response pathway targets, including HSF1 and Hsp70. Clin Cancer Res; 18(1); 64-76.

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70. 70

    Gestwicki, J. E. and Shao, H. (2019) Inhibitors and Chemical Probes for Molecular Chaperone Networks. J. Biol. Chem. 294 (6), 2151– 2161,  DOI: 10.1074/jbc.TM118.002813

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    72

    Inhibitors and chemical probes for molecular chaperone networks

    Gestwicki, Jason E.; Shao, Hao

    Journal of Biological Chemistry (2019), 294 (6), 2151-2161CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    A review. The mol. chaperones are central mediators of protein homeostasis. In that role, they engage in widespread protein-protein interactions (PPIs) with each other and with their "client" proteins. Together, these PPIs form the backbone of a network that ensures proper vigilance over the processes of protein folding, trafficking, quality control, and degrdn. The core chaperones, such as the heat shock proteins Hsp60, Hsp70, and Hsp90, are widely expressed in most tissues, yet there is growing evidence that the PPIs among them may be re-wired in disease conditions. This possibility suggests that these PPIs, and perhaps not the individual chaperones themselves, could be compelling drug targets. Indeed, recent efforts have yielded small mols. that inhibit (or promote) a subset of inter-chaperone PPIs. These chem. probes are being used to study chaperone networks in a range of models, and the successes with these approaches have inspired a community-wide objective to produce inhibitors for a broader set of targets. In this Review, we discuss progress toward that goal and point out some of the challenges ahead.

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71. 71

    Trager, W. and Jensen, J. B. (1976) Human Malaria Parasites in Continuous Culture. Science (Washington, DC, U. S.) 193 (4254), 673– 675,  DOI: 10.1126/science.781840

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    73

    Human malaria parasites in continuous culture

    Trager W; Jensen J B

    Science (New York, N.Y.) (1976), 193 (4254), 673-5 ISSN:0036-8075.

    Plasmodium falciparum can now be maintained in continuous culture in human erythrocytes incubated at 38 degrees C in RPMI 1640 medium with human serum under an atmosphere with 7 percent carbon dioxide and low oxygen (1 or 5 percent). The original parasite material, derived from an infected Aotus trivirgatus monkey, was diluted more than 100 million times by the addition of human erythrocytes at 3- or 4-day intervals. The parasites continued to reproduce in their normal asexual cycle of approximately 48 hours but were no longer highly synchronous. The have remained infective to Aotus.

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72. 72

    Ploemen, I. H., Prudêncio, M., Douradinha, B. G., Ramesar, J., Fonager, J., van Gemert, G. J., Luty, A. J., Hermsen, C. C., Sauerwein, R. W., Baptista, F. G., Mota, M. M., Waters, A. P., Que, I., Lowik, C. W., Khan, S. M., C.J. Janse, B. M. F.-F. (2009) Visualization and Quantitative Analysis of the Rodent Malaria Liver Stage by Real Time Imaging. PLoS One 4 (11), e7881  DOI: 10.1371/journal.pone.0007881

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    Pimenta, P. F. P., Orfano, A. S., Bahia, A. C., Duarte, A. P. M., Ríos-Velásquez, C. M., Melo, F. F., Pessoa, F. A. C., Oliveira, G. A., Campos, K. M. M., Villegas, L. M., Rodrigues, N. B., Nacif-pimenta, R., Simões, R. C., Monteiro, W. M., Amino, R., Traub-cseko, Y. M., Lima, J. B. P., Barbosa, M. G. V, Lacerda, M. V. G., Tadei, W. P., and Secundino, N. F. C. (2015) An Overview of Malaria Transmission from the Perspective of Amazon Anopheles Vectors. Mem. Inst. Oswaldo Cruz 110 (1), 23– 47,  DOI: 10.1590/0074-02760140266

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    An overview of malaria transmission from the perspective of Amazon Anopheles vectors

    Pimenta Paulo F P; Orfano Alessandra S; Duarte Ana P M; Melo Fabricio F; Oliveira Giselle A; Villegas Luis Martinez; Rodrigues Nilton Barnabe; Nacif-Pimenta Rafael; Bahia Ana C; Traub-Cseko Yara M; Rios-Velasquez Claudia M; Pessoa Felipe A C; Campos Keillen M M; Monteiro Wuelton M; Lima Jose B P; Barbosa Maria G V; Lacerda Marcus V G; Simoes Rejane C; Amino Rogerio

    Memorias do Instituto Oswaldo Cruz (2015), 110 (1), 23-47 ISSN:.

    In the Americas, areas with a high risk of malaria transmission are mainly located in the Amazon Forest, which extends across nine countries. One keystone step to understanding the Plasmodium life cycle in Anopheles species from the Amazon Region is to obtain experimentally infected mosquito vectors. Several attempts to colonise Anopheles species have been conducted, but with only short-lived success or no success at all. In this review, we review the literature on malaria transmission from the perspective of its Amazon vectors. Currently, it is possible to develop experimental Plasmodium vivax infection of the colonised and field-captured vectors in laboratories located close to Amazonian endemic areas. We are also reviewing studies related to the immune response to P. vivax infection of Anopheles aquasalis, a coastal mosquito species. Finally, we discuss the importance of the modulation of Plasmodium infection by the vector microbiota and also consider the anopheline genomes. The establishment of experimental mosquito infections with Plasmodium falciparum, Plasmodium yoelii and Plasmodium berghei parasites that could provide interesting models for studying malaria in the Amazonian scenario is important. Understanding the molecular mechanisms involved in the development of the parasites in New World vectors is crucial in order to better determine the interaction process and vectorial competence.

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74. 74

    Hartwig, C. L. (2013) BYBR Green I-Based Parasite Growth Inhibition Assay for Measurement of Antimalarial Drug Susceptibility in Plasmodium Falciparum. Methods in Malaria Research, pp 122– 129.

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75. 75

    Dearnley, M. K., Yeoman, J. A., Hanssen, E., Kenny, S., Turnbull, L., Whitchurch, C. B., Tilley, L., and Dixon, M. W. A. (2012) Origin, Composition, Organization and Function of the Inner Membrane Complex of Plasmodium Falciparum Gametocytes. J. Cell Sci. 125 (8), 2053– 2063,  DOI: 10.1242/jcs.099002

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    77

    Origin, composition, organization and function of the inner membrane complex of Plasmodium falciparum gametocytes

    Dearnley, Megan K.; Yeoman, Jeffrey A.; Hanssen, Eric; Kenny, Shannon; Turnbull, Lynne; Whitchurch, Cynthia B.; Tilley, Leann; Dixon, Matthew W. A.

    Journal of Cell Science (2012), 125 (8), 2053-2063CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)

    The most virulent of the human malaria parasites, Plasmodium falciparum, undergoes a remarkable morphol. transformation as it preps. itself for sexual reprodn. and transmission via mosquitoes. Indeed P. falciparum is named for the unique falciform or crescent shape of the mature sexual stages. Once the metamorphosis is completed, the mature gametocyte releases from sequestration sites and enters the circulation, thus making it accessible to feeding mosquitoes. Early ultrastructural studies showed that gametocyte elongation is driven by the assembly of a system of flattened cisternal membrane compartments underneath the parasite plasma membrane and a supporting network of microtubules. Here we describe the mol. compn. and origin of the sub-pellicular membrane complex, and show that it is analogous to the inner membrane complex, an organelle with structural and motor functions that is well conserved across the apicomplexa. We identify novel crosslinking elements that might help stabilize the inner membrane complex during gametocyte development. We show that changes in gametocyte morphol. are assocd. with an increase in cellular deformability and postulate that this enables the gametocytes to circulate in the bloodstream without being detected and removed by the mech. filtering mechanisms in the spleen of the host.

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    Dixon, M. W. A., Dearnley, M. K., Hanssen, E., Gilberger, T., and Tilley, L. (2012) Shape-Shifting Gametocytes: How and Why Does P. Falciparum Go Banana-Shaped ?. Trends Parasitol. 28 (11), 471– 478,  DOI: 10.1016/j.pt.2012.07.007

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    78

    Shape-shifting gametocytes: how and why does P. falciparum go banana-shaped?

    Dixon Matthew W A; Dearnley Megan K; Hanssen Eric; Gilberger Tim; Tilley Leann

    Trends in parasitology (2012), 28 (11), 471-8 ISSN:.

    Plasmodium falciparum is named for the crescent or falciform shape it adopts when preparing to undergo transfer to a mosquito vector. By contrast, gametocytes of the other (less virulent) human malaria parasites retain a more rounded shape. We describe the machinery that elongates falciparum gametocytes and discuss its relation with the machinery that elongates the invasive zoites. We address the question - why do falciparum malaria gametocytes go banana-shaped? The answer may lie in the finding that gametocyte maturation is associated with an increase in cellular deformability. The shape-shifting ability of gametocytes may facilitate the sequestration of early-stage gametocytes, while enabling late-stage gametocytes to circulate in the blood stream without being removed by the mechanical filtering mechanisms in the host spleen.

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77. 77

    Schneekloth, J. S., Fonseca, F. N., Koldobskiy, M., Mandal, A., Deshaies, R., Sakamoto, K., and Crews, C. M. (2004) Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation. J. Am. Chem. Soc. 126 (12), 3748– 3754,  DOI: 10.1021/ja039025z

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    79

    Chemical genetic control of protein levels: selective in vivo targeted degradation

    Schneekloth, John S., Jr.; Fonseca, Fabiana N.; Koldobskiy, Michael; Mandal, Amit; Deshaies, Raymond; Sakamoto, Kathleen; Crews, Craig M.

    Journal of the American Chemical Society (2004), 126 (12), 3748-3754CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Genetic loss of function anal. is a powerful method for the study of protein function. However, some cell biol. questions are difficult to address using traditional genetic strategies often due to the lack of appropriate genetic model systems. Here, we present a general strategy for the design and syntheses of mols. capable of inducing the degrdn. of selected proteins in vivo via the ubiquitin-proteasome pathway. Western blot and fluorometric analyses indicated the loss of two different targets: green fluorescent protein (GFP) fused with FK506 binding protein (FKBP12) and GFP fused with the androgen receptor (AR), after treatment with PROteolysis TArgeting Chimeric mols. (PROTACS) incorporating a FKBP12 ligand and dihydrotestosterone, resp. These are the first in vivo examples of direct small mol.-induced recruitment of target proteins to the proteasome for degrdn. upon addn. to cultured cells. Moreover, PROTAC-mediated protein degrdn. offers a general strategy to create "chem. knockouts," thus opening new possibilities for the control of protein function.

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78. 78

    Magariños, M. P., Carmona, S. J., Crowther, G. J., Ralph, S. A., Roos, D. S., Shanmugam, D., Van Voorhis, W. C., and Agüero, F. (2012) TDR Targets: A Chemogenomics Resource for Neglected Diseases. Nucleic Acids Res. 40 (D1), D1118– 1127,  DOI: 10.1093/nar/gkr1053

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    80

    TDR Targets: a chemogenomics resource for neglected diseases

    Magarinos, Maria P.; Carmona, Santiago J.; Crowther, Gregory J.; Ralph, Stuart A.; Roos, David S.; Shanmugam, Dhanasekaran; Van Voorhis, Wesley C.; Agueero, Fernan

    Nucleic Acids Research (2012), 40 (D1), D1118-D1127CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)

    The TDR Targets Database (http://tdrtargets.org) has been designed and developed as an online resource to facilitate the rapid identification and prioritization of mol. targets for drug development, focusing on pathogens responsible for neglected human diseases. The database integrates pathogen specific genomic information with functional data (e.g. expression, phylogeny, essentiality) for genes collected from various sources, including literature curation. This information can be browsed and queried using an extensive web interface with functionalities for combining, saving, exporting and sharing the query results. Target genes can be ranked and prioritized using numerical wts. assigned to the criteria used for querying. In this report we describe recent updates to the TDR Targets database, including the addn. of new genomes (specifically helminths), and integration of chem. structure, property and bioactivity information for biol. ligands, drugs and inhibitors and cheminformatic tools for querying and visualizing these chem. data. These changes greatly facilitate exploration of linkages (both known and predicted) between genes and small mols., yielding insight into whether particular proteins may be druggable, effectively allowing the navigation of chem. space in a genomics context.

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    Hoepfner, D., Helliwell, S. B., Sadlish, H., Schuierer, S., Filipuzzi, I., Brachat, S., Bhullar, B., Plikat, U., Abraham, Y., Altorfer, M., Aust, T., Baeriswyl, L., Cerino, R., Chang, L., Estoppey, D., Eichenberger, J., Frederiksen, M., Hartmann, N., Hohendahl, A., Knapp, B., Krastel, P., Melin, N., Nigsch, F., Oakeley, E. J., Petitjean, V., Petersen, F., Riedl, R., Schmitt, E. K., Staedtler, F., Studer, C., Tallarico, J. A., Wetzel, S., Fishman, M. C., Porter, J. A., and Movva, N. R. (2014) High-Resolution Chemical Dissection of a Model Eukaryote Reveals Targets, Pathways and Gene Functions. Microbiol. Res. 169 (2–3), 107– 120,  DOI: 10.1016/j.micres.2013.11.004

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    81

    High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions

    Hoepfner, Dominic; Helliwell, Stephen B.; Sadlish, Heather; Schuierer, Sven; Filipuzzi, Ireos; Brachat, Sophie; Bhullar, Bhupinder; Plikat, Uwe; Abraham, Yann; Altorfer, Marc; Aust, Thomas; Baeriswyl, Lukas; Cerino, Raffaele; Chang, Lena; Estoppey, David; Eichenberger, Juerg; Frederiksen, Mathias; Hartmann, Nicole; Hohendahl, Annika; Knapp, Britta; Krastel, Philipp; Melin, Nicolas; Nigsch, Florian; Oakeley, Edward J.; Petitjean, Virginie; Petersen, Frank; Riedl, Ralph; Schmitt, Esther K.; Staedtler, Frank; Studer, Christian; Tallarico, John A.; Wetzel, Stefan; Fishman, Mark C.; Porter, Jeffrey A.; Movva, N. Rao

    Microbiological Research (2014), 169 (2-3), 107-120CODEN: MCRSEJ; ISSN:0944-5013. (Elsevier GmbH)

    Due to evolutionary conservation of biol., exptl. knowledge captured from genetic studies in eukaryotic model organisms provides insight into human cellular pathways and ultimately physiol. Yeast chemogenomic profiling is a powerful approach for annotating cellular responses to small mols. Using an optimized platform, we provide the relative sensitivities of the heterozygous and homozygous deletion collections for nearly 1800 biol. active compds. The data quality enables unique insights into pathways that are sensitive and resistant to a given perturbation, as demonstrated with both known and novel compds. We present examples of novel compds. that inhibit the therapeutically relevant fatty acid synthase and desaturase (Fas1p and Ole1p), and demonstrate how the individual profiles facilitate hypothesis-driven expts. to delineate compd. mechanism of action. Importantly, the scale and diversity of tested compds. yields a dataset where the no. of modulated pathways approaches satn. This resource can be used to map novel biol. connections, and also identify functions for unannotated genes. We validated hypotheses generated by global two-way hierarchical clustering of profiles for (i) novel compds. with a similar mechanism of action acting upon microtubules or vacuolar ATPases, and (ii) an un-annotated ORF, YIL060w, that plays a role in respiration in the mitochondria. Finally, we identify and characterize background mutations in the widely used yeast deletion collection which should improve the interpretation of past and future screens throughout the community. This comprehensive resource of cellular responses enables the expansion of our understanding of eukaryotic pathway biol.

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    Love, M. I., Huber, W., and Anders, S. (2014) Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2. Genome Biol. 15 (12), 1– 21,  DOI: 10.1186/s13059-014-0550-8

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81. 81

    Smith, A. M., Durbic, T., Oh, J., Urbanus, M., Proctor, M., Heisler, L. E., Giaever, G., and Nislow, C. (2011) Competitive Genomic Screens of Barcoded Yeast Libraries. J. Vis. Exp. 54, 2864,  DOI: 10.3791/2864

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82. 82

    Silva, N. S.M., Bertolino-Reis, D. E., Dores-Silva, P. R., Anneta, F. B., Seraphim, T. V., Barbosa, L. R.S., and Borges, J. C. (2020) Structural Studies of the Hsp70/Hsp90 Organizing Protein of Plasmodium Falciparum and Its Modulation of Hsp70 and Hsp90 ATPase Activities. Biochim. Biophys. Acta, Proteins Proteomics 1868, 140282,  DOI: 10.1016/j.bbapap.2019.140282

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    84

    Structural studies of the Hsp70/Hsp90 organizing protein of Plasmodium falciparum and its modulation of Hsp70 and Hsp90 ATPase activities

    Silva, Noeli S. M.; Bertolino-Reis, Dayane E.; Dores-Silva, Paulo R.; Anneta, Fatima B.; Seraphim, Thiago V.; Barbosa, Leandro R. S.; Borges, Julio C.

    Biochimica et Biophysica Acta, Proteins and Proteomics (2020), 1868 (1), 140282CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B.V.)

    HOP is a cochaperone belonging to the foldosome, a system formed by the cytoplasmic Hsp70 and Hsp90 chaperones. HOP acts as an adapter protein capable of transferring client proteins from the first to the second mol. chaperone. HOP is a modular protein that regulates the ATPase activity of Hsp70 and Hsp90 to perform its function. To obtain more detailed information on the structure and function of this protein, we produced the recombinant HOP of Plasmodium falciparum (PfHOP). The protein was obtained in a folded form, with a high content of α-helix secondary structure. Unfolding expts. showed that PfHOP unfolds through two transitions, suggesting the presence of at least two domains with different stabilities. In addn., PfHOP primarily behaved as an elongated dimer in equil. with the monomer. Small-angle X-ray scattering data corroborated this interpretation and led to the reconstruction of a PfHOP ab initio model as a dimer. Finally, the PfHOP protein was able to inhibit and to stimulate the ATPase activity of the recombinant Hsp90 and Hsp70-1, resp., of P. falciparum. Our results deepened the knowledge of the structure and function of PfHOP and further clarified its participation in the P. falciparum foldosome.

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83. 83

    Silva, N. S.M., Seraphim, T. V., Minari, K., Barbosa, L. R.S., and Borges, J. C. (2018) Comparative Studies of the Low-Resolution Structure of Two P23 Co-Chaperones for Hsp90 Identified in Plasmodium Falciparum Genome. Int. J. Biol. Macromol. 108, 193– 204,  DOI: 10.1016/j.ijbiomac.2017.11.161

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    85

    Comparative studies of the low-resolution structure of two p23 co-chaperones for Hsp90 identified in Plasmodium falciparum genome

    Silva, Noeli S. M.; Seraphim, Thiago V.; Minari, Karine; Barbosa, Leandro R. S.; Borges, Julio C.

    International Journal of Biological Macromolecules (2018), 108 (), 193-204CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)

    The p23 proteins are small acidic proteins that aid the functional cycle of the Hsp90 mol. chaperone. Such co-chaperone acts by temporarily inhibiting the ATPase activity of Hsp90 and exhibits intrinsic chaperone activity, suggesting independent roles. A search for p23 in the Plasmodium falciparum genome led to the identification of two putative proteins showing 13% identity to each other and approx. 20% identity to human p23. To understand the presence of two p23 proteins in this organism, we generated recombinant p23 proteins (Pfp23A and Pfp23B) and investigated their structure and function. The proteins presented some similarities and dissimilarities in structural contents and showed different chem. and thermal stabilities, with Pfp23A being more stable than Pfp23B, suggesting that these proteins may present different functions in this organism. Both Pfp23 proteins behaved as elongated monomers in soln. and were capable of preventing the thermal-induced aggregation of model client proteins with different efficiencies. Finally, the Pfp23 proteins inhibited the ATPase activity of recombinant P. falciparum Hsp90 (PfHsp90). These results validate the studied proteins as p23 proteins and co-chaperones of PfHsp90.

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    Seraphim, T. V., Gava, L. M., Mokry, D. Z., Cagliari, T. C., Barbosa, L. R. S., Ramos, C. H. I., and Borges, J. C. (2015) The C-Terminal Region of the Human P23 Chaperone Modulates Its Structure and Function. Arch. Biochem. Biophys. 565, 57– 67,  DOI: 10.1016/j.abb.2014.10.015

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    86

    The C-terminal region of the human p23 chaperone modulates its structure and function

    Seraphim, Thiago V.; Gava, Lisandra M.; Mokry, David Z.; Cagliari, Thiago C.; Barbosa, Leandro R. S.; Ramos, Carlos H. I.; Borges, Julio C.

    Archives of Biochemistry and Biophysics (2015), 565 (), 57-67CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)

    The p23 protein is a chaperone widely involved in protein homeostasis, well known as an Hsp90 co-chaperone since it also controls the Hsp90 chaperone cycle. Human p23 includes a β-sheet domain, responsible for interacting with Hsp90; and a charged C-terminal region whose function is not clear, but seems to be natively unfolded. p23 can undergo caspase-dependent proteolytic cleavage to form p19 (p231-142), which is involved in apoptosis, while p23 has anti-apoptotic activity. To better elucidate the function of the human p23 C-terminal region, we studied comparatively the full-length human p23 and three C-terminal truncation mutants: p231-117; p231-131 and p231-142. Our data indicate that p23 and p19 have distinct characteristics, whereas the other two truncations behave similarly, with some differences to p23 and p19. We found that part of the C-terminal region can fold in an α-helix conformation and slightly contributes to p23 thermal-stability, suggesting that the C-terminal interacts with the β-sheet domain. As a whole, our results suggest that the C-terminal region of p23 is crit. for its structure-function relationship. A mechanism where the human p23 C-terminal region behaves as an activation/inhibition module for different p23 activities is proposed.

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