MK-7602: a potent multi-stage dual-targeting antimalarial

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Substantial global malaria burden necessitates novel antimalarials due to increasing parasite resistance.
• Existing treatments face challenges from drug-resistant malaria strains, demanding new mechanisms of action.

Purpose of the Study:

• To develop and characterize a novel antimalarial compound targeting Plasmodium aspartic proteases.
• To evaluate the efficacy and resistance profile of the new compound, MK-7602.

Main Methods:

• High-throughput screening and medicinal chemistry optimization were employed.
• In vitro and in vivo testing were conducted to assess MK-7602's antimalarial activity.
• MK-7602 was evaluated as a dual inhibitor of plasmepsins IX and X.

Main Results:

• MK-7602 is a dual sub-nanomolar inhibitor of plasmepsins IX and X across multiple Plasmodium species.
• The compound demonstrated activity against liver and blood stages, blocked parasite transmission, and possessed favorable pharmacokinetics and safety.
• MK-7602 exhibited a high barrier to resistance and lacked cross-resistance with existing antimalarial-resistant strains.

Conclusions:

• MK-7602 represents a new class of antimalarial with a novel mechanism, offering potential for treating uncomplicated and drug-resistant malaria.
• Clinical evaluation of MK-7602 against Plasmodium falciparum is currently underway.