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acs.jmedchem.3c00812 (1).pdf (6.74 MB)

Macrocyclic peptidomimetic plasmepsin X inhibitors with potent in vitro and in vivo antimalarial activity.

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journal contribution
posted on 2023-08-10, 10:31 authored by Vadims Kovada, Chrislaine Withers-Martinez, Raitis Bobrovs, Hele̅na Ce̅rule, Edgars Liepins, Solveiga Grinberga, Fiona Hackett, Christine R Collins, Agrita Kreicberga, María Belén Jiménez-Díaz, Iñigo Angulo-Barturen, Dace Rasina, Edgars Suna, 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.


Crick (Grant ID: CC2129, Grant title: Blackman CC2129)