High-Content Phenotypic Screen of a Focused TCAMS Drug Library Identifies Novel Disruptors of the Malaria Parasite Calcium DynamicsClick to copy article linkArticle link copied!
- Wanni ChiaWanni ChiaLaboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, and Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, S117545, SingaporeMore by Wanni Chia
- Maria G. Gomez-LorenzoMaria G. Gomez-LorenzoGlobal Health Discovery Incubator Unit, Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, SpainMore by Maria G. Gomez-Lorenzo
- Isabel CastelloteIsabel CastelloteGlobal Health Discovery Incubator Unit, Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, SpainMore by Isabel Castellote
- Jie Xin TongJie Xin TongLaboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, and Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, S117545, SingaporeMore by Jie Xin Tong
- Rajesh ChandramohanadasRajesh ChandramohanadasLaboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, and Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, S117545, SingaporeMore by Rajesh Chandramohanadas
- Trang Thi Thu ChuTrang Thi Thu ChuLaboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, and Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, S117545, SingaporeMore by Trang Thi Thu Chu
- Wanxiang ShenWanxiang ShenDepartment of Pharmacy, National University of Singapore, 18 Science Drive 4, S117543, SingaporeMore by Wanxiang Shen
- Mei Lin GoMei Lin GoDepartment of Pharmacy, National University of Singapore, 18 Science Drive 4, S117543, SingaporeMore by Mei Lin Go
- Cristina de CozarCristina de CozarGlobal Health Discovery Incubator Unit, Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, SpainMore by Cristina de Cozar
- Benigno CrespoBenigno CrespoGlobal Health Discovery Incubator Unit, Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, SpainMore by Benigno Crespo
- Maria J. AlmelaMaria J. AlmelaGlobal Health Discovery Incubator Unit, Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, SpainMore by Maria J. Almela
- Fernando Neria-SerranoFernando Neria-SerranoGlobal Health Discovery Incubator Unit, Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, SpainMore by Fernando Neria-Serrano
- Virginia FrancoVirginia FrancoGlobal Health Discovery Incubator Unit, Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, SpainMore by Virginia Franco
- Francisco-Javier GamoFrancisco-Javier GamoGlobal Health Discovery Incubator Unit, Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, SpainMore by Francisco-Javier Gamo
- Kevin S. W. Tan*Kevin S. W. Tan*Email: [email protected]Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, and Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, S117545, SingaporeMore by Kevin S. W. Tan
Abstract
The search for new antimalarial drugs with unexplored mechanisms of action is currently one of the main objectives to combat the resistance already in the clinic. New drugs should target specific mechanisms that once initiated lead inevitably to the parasite’s death and clearance and cause minimal toxicity to the host. One such new mode of action recently characterized is to target the parasite’s calcium dynamics. Disruption of the calcium homeostasis is associated with compromised digestive vacuole membrane integrity and release of its contents, leading to programmed cell death-like features characterized by loss of mitochondrial membrane potential and DNA degradation. Intriguingly, chloroquine (CQ)-treated parasites were previously reported to exhibit such cellular features. Using a high-throughput phenotypic screen, we identified 158 physiological disruptors (hits) of parasite calcium distribution from a small subset of approximately 3000 compounds selected from the GSK TCAMS (Tres Cantos Anti-Malarial Set) compound library. These compounds were then extensively profiled for biological activity against various CQ- and artemisinin-resistant Plasmodium falciparum strains and stages. The hits were also examined for cytotoxicity, speed of antimalarial activity, and their possible inhibitory effects on heme crystallization. Overall, we identified three compounds, TCMDC-136230, -125431, and -125457, which were potent in inducing calcium redistribution but minimally inhibited heme crystallization. Molecular superimposition of the molecules by computational methods identified a common pharmacophore, with the best fit assigned to TCMDC-125457. There were low cytotoxicity or CQ cross-resistance issues for these three compounds. IC50 values of these three compounds were in the low micromolar range. In addition, TCMDC-125457 demonstrated high efficacy when pulsed in a single-dose combination with artesunate against tightly synchronized artemisinin-resistant ring-stage parasites. These results should add new drug options to the current armament of antimalarial drugs as well as provide promising starting points for development of drugs with non-classical modes of action.
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