Development of Highly Selective Epoxyketone-based Plasmodium Proteasome Inhibitors with Negligible Cytotoxicity

Almaliti, J.; Fajtova, P.; Calla, J.; LaMonte, G. M.; Feng, M.; Rocamora, F.; Ottilie, S.; Glukhov, E.; Boura, E.; Suhandynata, R. T.; Momper, J. D.; Gilson, M. K.; Winzeler, E. A.; Gerwick, W. H.; O'Donoghue, A. J.

doi:10.1101/2022.08.06.502205

bioRxiv · 10.1101/2022.08.06.502205

Development of Highly Selective Epoxyketone-based Plasmodium Proteasome Inhibitors with Negligible Cytotoxicity

Almaliti, J.·Fajtova, P.·Calla, J.·LaMonte, G. M.·Feng, M.·Rocamora, F.·Ottilie, S.·Glukhov, E.·Boura, E.·Suhandynata, R. T.·Momper, J. D.·Gilson, M. K.·Winzeler, E. A.·Gerwick, W. H.·O'Donoghue, A. J.

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Abstract

Here we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in vitro potency for blood-stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,600-fold greater selectivity for erythrocytic-stage P. falciparum over HepG2 cells, which is largely driven by the accommodation of the parasite proteasome for a O_SCPLOWDC_SCPLOW-amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti-malarial drugs.

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Almaliti, J., Fajtova, P., Calla, J., LaMonte, G. M., Feng, M., Rocamora, F., Ottilie, S., Glukhov, E., Boura, E., Suhandynata, R. T., Momper, J. D., Gilson, M. K., Winzeler, E. A., Gerwick, W. H., O'Donoghue, A. J.. 2022-08-07. Development of Highly Selective Epoxyketone-based Plasmodium Proteasome Inhibitors with Negligible Cytotoxicity. https://doi.org/10.1101/2022.08.06.502205

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