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

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.