Plasmodium falciparum, the parasite responsible for the deadliest form of malaria, affects millions of people each year. P. falciparum adopts a complicated life cycle where the parasite infects mosquito midgut epithelium, human hepatocytes and erythrocytes. Antimalarial drugs that target multiple life stages can block parasite development and transmission in a more effective manner and may help prevent the development of drug resistance. We previously identified that clemastine, an FDA-approved antihistamine, effectively inhibits the blood and liver stage with an unknown mechanism of action. As observed in our blood stage cultures, parasites treated with clemastine have delayed growth compared with a DMSO control and a human TRiC inhibitor HSF1A. At later time points, clemastine-treated parasites have a lowered ratio of late- stage schizonts, indicating that treatment leads to delayed development. Our proteomics assays suggest that clemastine targets the P. falciparum TCP-1 (TRiC/CCT) ring complex, a hetero-oligomeric complex required for the folding of actin and tubulin. Our findings show that clemastine destabilization of TRiC results in disorientation of microtubule filaments during Plasmodium asexual reproduction and an overall reduction in tubulin levels. Clemastine-induced disruption of tubulin formation is not seen in human host cells, indicating selectivity for targeting parasites. Overall, our study highlights selective targeting of Plasmodium TRiC protein-folding as a safe therapeutic strategy in controlling Plasmodium development. Further studies of pre-approved, dual-stage inhibitors like clemastine can reveal novel targets within Plasmodium in order to combat malaria.

Clemastine is an important inhibitor of Plasmodium parasite development

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.