2. Academic Validation
  3. Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitro and In Vivo Antimalarial Activity

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

  • J Med Chem. 2023 Aug 10;66(15):10658-10680. doi: 10.1021/acs.jmedchem.3c00812.
Vadims Kovada 1,  Chrislaine Withers-Martinez 2,  Raitis Bobrovs 1,  Hele Na Ce Rule 1,  Edgars Liepins 1,  Solveiga Grinberga 1,  Fiona Hackett 2,  Christine R Collins 2,  Agrita Kreicberga 1,  María Belén Jiménez-Díaz 3,  Iñigo Angulo-Barturen 3,  Dace Rasina 1,  Edgars Suna 1,  Kristaps Jaudzems 1,  Michael J Blackman 2 4,  Aigars Jirgensons 1
Affiliations

Affiliations

  • 1 Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia.
  • 2 Malaria Biochemistry Laboratory, The Francis Crick Institute, London NW1 1AT, United Kingdom.
  • 3 The Art of Discovery SL, Biscay Science and Technology Park, Derio, 48160 Bizkaia, Basque Country, Spain.
  • 4 Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, United Kingdom.
PMID: 37505188 DOI: 10.1021/acs.jmedchem.3c00812
Abstract

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.

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