The Invention of WM382, a Highly Potent PMIX/X Dual Inhibitor toward the Treatment of Malaria

Drug resistance to first-line antimalarials-including artemisinin-is increasing, resulting in a critical need for the discovery of new agents with novel mechanisms of action. In collaboration with the Walter and Eliza Hall Institute and with funding from the Wellcome Trust, a phenotypic screen of Merck's aspartyl protease inhibitor library identified a series of plasmepsin X (PMX) hits that were more potent than chloroquine. Inspired by a PMX homology model, efforts to optimize the potency resulted in the discovery of leads that, in addition to potently inhibiting PMX, also inhibit another essential aspartic protease, plasmepsin IX (PMIX). Further potency and pharmacokinetic profile optimization efforts culminated in the discovery of WM382, a very potent dual PMIX/X inhibitor with robust in vivo efficacy at multiple stages of the malaria parasite life cycle and an excellent resistance profile.

Automated summary

Drug resistance to antimalarials is increasing, highlighting the need for new drugs with novel mechanisms of action. A phenotypic screen identified a potent plasmepsin X inhibitor, which was further optimized to also inhibit plasmepsin IX. The resulting dual inhibitor showed excellent in vivo efficacy and resistance profile.