Novel Scaffold Unlocks Potent Cross-Peptidase and Cross-Species Inhibitors as Promising Antimalarial Agents

Mansouri, M; De Paoli, A; Giannangelo, C; Chowdury, M; Ngo, A; Shackleford, DM; Webb, CT; Lowes, KN; Creek, DJ; Charman, SA; Koning-Ward, TF; McGowan, S; Scammells, PJ

Author(s): Mansouri, M; De Paoli, A; Giannangelo, C; Chowdury, M; Ngo, A; Shackleford, DM; Webb, CT; Lowes, KN; Creek, DJ; Charman, SA; Koning-Ward, TF; McGowan, S; Scammells, PJ;
Details: Publication Year 2026-01-22,Volume 69,Issue #2,Page 1358-1386
Journal Title: Journal of Medicinal Chemistry
Abstract: Malaria remains a global health burden and the emergence of parasite-resistance to frontline drugs highlights an urgent need for new therapeutics with novel mechanisms of action. Inhibiting aminopeptidases, in particular the Plasmodium falciparum M1 and M17 aminopeptidases (PfA-M1 and PfA-M17 respectively) has been shown to cause parasite death. In this study, both ligand-based and structure-based design strategies were utilized to identify novel scaffolds that act as dual inhibitors of these enzymes. Structural studies supported the improved activity showing strong hydrophobic and additional hydrogen interactions between the new cores and the S1 pocket of the enzymes. These inhibitors were highly effective against Plasmodium vivax and Plasmodium berghei, showing cross-peptidase and cross-species activity while also retaining activity against multidrug resistant P. falciparum strains. Progression to in vivo efficacy studies showed reduction in parasitaemia in mice infected with P. berghei demonstrating encouraging prospects to develop suitable drug-like candidates for the treatment of malaria.
Publisher: ACS
Keywords: *Antimalarials/pharmacology/chemistry/therapeutic use/chemical synthesis; Animals; Plasmodium falciparum/drug effects/enzymology; Plasmodium berghei/drug effects/enzymology; Mice; Structure-Activity Relationship; Malaria/drug therapy; *Protease Inhibitors/pharmacology/chemistry/therapeutic use; Plasmodium vivax/drug effects/enzymology; *Aminopeptidases/antagonists & inhibitors/metabolism; Humans
Research Division(s): New Medicines and Diagnostics
PubMed ID: HTTPS:/41525497
Publisher's Version: https://doi.org/10.1021/acs.jmedchem.5c02743
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-29 02:00:44

Last Modified: 2026-01-29 02:01:03