Image

Manuel de Lera Ruiz - Merck

Host:  Ramesh Giri (865-0063)

“The Anatomy of a Drug: What Makes MK-7602 an Effective Antimalarial?”

Abstract:

Malaria is a devastating disease that affects over half a million people each year mostly children under five years old and pregnant women.

Antimalarial drug discovery by and large is focused on the identification of novel drugs to treat and prevent the disease due to the emergence and spread of Plasmodium strains resistant to existing medicines. In particular arteminisin resistance which has now spread from South East Asia and is firmly established in Africa (as reported at ASTMH in Seattle Oct 2022).

The Merck Research Labs (led by Dr. David Olsen) and the Walter and Eliza Hall Institute of Medical Research (WEHI) (led by Prof. Alan Cowman), have teamed up to invent novel drug candidates by targeting the Plasmodium parasite via newly identified essential aspartyl proteases. The team has been greatly assisted in this endeavor with generous funding for the collaboration from the Wellcome Trust (UK). The team was successful at identifying potent dual protease targeting hits that lead to the identification of an important tool compound WM382 with subnanomolar inhibitory potency in vitro. This was accomplished through targeted phenotypic screening and structure-guided medicinal chemistry to optimize orphan (mechanism of action unknown) hit compounds. WM382 was also used to establish impressive in vivo proof-of-concept efficacy not only on blood stage parasitemia but also potent pharmacodynamic effects in the sexual/mosquito and liver stages of replication. Finally, Justin Boddey’s team at WEHI determined that defective parasites under WM382 drug coverage yield some interesting immunological effects in mice in vivo. Further optimization of potency and pharmacokinetic and selectivity profiles resulted in the invention of clinical compound MK-7602, a very potent PMIX/X dual inhibitor with robust in vivo efficacy in mice at the three stages of the malaria parasite lifecycle and excellent off-target activity and resistance profiles.