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bioRxiv · 10.1101/2024.08.12.607553

A fast-acting inhibitor of blood-stage P. falciparum with mechanism distinct from artemisinin and chloroquine

Kabeche, S.·Meister, T.·Yeh, E.
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Abstract

Artemisinins are first-line treatment for malaria, prized for their extremely fast reduction of parasite load in patients. New fast-acting antimalarial compounds are urgently needed to counter artemisinin resistance, but the fast parasite reduction observed with artemisinins is rare among antimalarial compounds. Here we show that MMV1580853 has a very fast in vitro killing rate, comparable to that of dihydroartemisinin. Near-complete parasite growth inhibition was observed within 1 hour of treatment with MMV1580853 and dihydroartemisinin, while chloroquine, another fast-acting antimalarial, showed partial growth inhibition after 1h. MMV1580853 was reported to inhibit prenyltransferases, but its fast killing rate is inconsistent with this mechanism-of-action and we were unable to validate any of 3 annotated P. falciparum prenyltransferases as MMV1580853 targets. MMV1580853 also did not phenocopy the inhibition phenotype of either chloroquine or dihydroartemisinin. These results indicate that MMV1580853 has a distinct mechanism-of-action leading to a very fast killing rate. MMV1580853 compound development and investigation of its mechanism-of-action will be critical avenues in the search for drugs matching the remarkable clinical efficacy of artemisinin.

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Kabeche, S., Meister, T., Yeh, E.. 2024-08-12. A fast-acting inhibitor of blood-stage P. falciparum with mechanism distinct from artemisinin and chloroquine. https://doi.org/10.1101/2024.08.12.607553

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