A small-molecule myosin inhibitor as a targeted multi-stage antimalarial

Trivedi, D. V.; Karabina, A.; Bergnes, G.; Racca, A.; Wander, H.; Jung, S.; Mittal, N.; Huijs, T.; Ouchida, S.; Ruijgrok, P. V.; Song, D.; Wittlin, S.; Mukherjee, P.; Chakraborty, A.; Winzeler, E. A.; Burrows, J. N.; Laleu, B.; Spudich, A.; Ruppel, K.; Dechering, K.; Nag, S.; Spudich, J.

doi:10.1101/2022.09.09.507317

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bioRxiv · 10.1101/2022.09.09.507317

A small-molecule myosin inhibitor as a targeted multi-stage antimalarial

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Abstract

Malaria is a devastating disease that resulted in an estimated 627,000 deaths in 2020. About 80% of those deaths were among children under the age of five. Our approach is to develop small molecule inhibitors against cytoskeletal targets that are vital components of parasite function, essential at multiple stages of parasite infection, can be targeted with high specificity, and are highly druggable. Here we describe KNX-115, which inhibits purified Plasmodium falciparum myosin A (PfMyoA) actin-activated ATPase with a potency in the 10s of nanomolar range and >50-fold selectivity against cardiac, skeletal, and smooth muscle myosins. KNX-115 inhibits the blood and liver stages of Plasmodium with an EC50 of about 100 nanomolar, with negligible liver cell toxicity. In addition, KNX-115 inhibits sporozoite cell traversal and blocks the gametocyte to oocyst conversion in the mosquito. KNX-115 displays a similar killing profile to pyrimethamine and parasites are totally killed after 96 hours of treatment. In line with its novel mechanism of action, KNX-115 is equally effective at inhibiting a panel of Plasmodium strains resistant to experimental and marketed antimalarials. In vitro evolution data likely suggests a refractory potential of KNX-115 in developing parasite resistance.

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Trivedi, D. V., Karabina, A., Bergnes, G., Racca, A., Wander, H., Jung, S., Mittal, N., Huijs, T., Ouchida, S., Ruijgrok, P. V., Song, D., Wittlin, S., Mukherjee, P., Chakraborty, A., Winzeler, E. A., Burrows, J. N., Laleu, B., Spudich, A., Ruppel, K., Dechering, K., Nag, S., Spudich, J.. 2022-09-10. A small-molecule myosin inhibitor as a targeted multi-stage antimalarial. https://doi.org/10.1101/2022.09.09.507317

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