Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitro and In Vivo Antimalarial Activity

Journal of Medicinal Chemistry 2023
Vadims Kovada, Chrislaine Withers-Martinez, Raitis Bobrovs, Helēna Cīrule, Edgars Liepiņš, Solveiga Grinberga, Fiona Hackett, Christine R. Collins, Agrita Kreicberga, Maria Belen Jimez-Diaz, Inigo Angulo-Barturen, Dace Rasiņa, Edgars Sūna, Kristaps Jaudzems, Michael J. Blackman, Aigars Jirgensons

The Plasmodium falciparum aspartic protease plasmepsin X (PMX) is essential for the egress of invasive merozoite forms of the parasite. PMX has therefore emerged as a new potential antimalarial target. Building on peptidic amino alcohols originating from a phenotypic screening hit, we have here developed a series of macrocyclic analogues as PMX inhibitors. Incorporation of an extended linker between the S1 phenyl group and S3 amide led to a lead compound that displayed a 10-fold improved PMX inhibitory potency and a 3-fold improved half-life in microsomal stability assays compared to the acyclic analogue. The lead compound was also the most potent of the new macrocyclic compounds in in vitro parasite growth inhibition. Inhibitor 7k cleared blood-stage P. falciparum in a dose-dependent manner when administered orally to infected humanized mice. Consequently, lead compound 7k represents a promising orally bioavailable molecule for further development as a PMX-targeting antimalarial drug.

DOI
10.1021/acs.jmedchem.3c00812
Hipersaite
https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00812

Kovada, V., Withers-Martinez, C., Bobrovs, R., Cīrule, H., Liepiņš, E., Grinberga, S., Hackett, F., Collins, C., Kreicberga, A., Jimez-Diaz, M., Angulo-Barturen, I., Rasiņa, D., Sūna, E., Jaudzems, K., Blackman, M., Jirgensons, A. Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitro and In Vivo Antimalarial Activity. Journal of Medicinal Chemistry, 2023, Vol. 66, No. 15, 10658.-10680.lpp. ISSN 0022-2623. Pieejams: doi:10.1021/acs.jmedchem.3c00812

Publikācijas valoda
English (en)