Activity Refinement and Property Assessment of Peptidomimetics with Potent Antimalarial Activity That Target...

Plasmepsin V is an essential aspartyl protease that cleaves the Plasmodium export element in proteins targeted for export from Plasmodium parasites into the host red blood cell. Substrate-mimicking peptidomimetics have been developed that potently inhibit plasmepsin V but show modest parasite activity. To advance these inhibitors, we optimized their potency by introducing a 2-chloro aryl group at P2 and an N-terminal sulfonamide that yielded WM960, which showed markedly improved plasmepsin V inhibition while retaining high selectivity over plasmepsin IX and X and human aspartyl proteases. WM960 also demonstrated enhanced activity against asexual blood-stage parasites and effectively suppressed protein export. However, WM960 displayed low metabolic stability and limited systemic exposure in mice, highlighting the need to improve pharmacokinetic properties in future development of peptidomimetic plasmepsin V targeted antimalarials.