Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitro and In Vivo Antimalarial Activity

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• The Plasmodium falciparum aspartic protease plasmepsin X (PMX) is crucial for parasite egress.
• PMX represents a potential drug target for malaria treatment.

Purpose of the Study:

• To develop novel macrocyclic inhibitors of PMX.
• To identify potent and orally bioavailable antimalarial drug candidates.

Main Methods:

• Phenotypic screening yielded peptidic amino alcohol starting points.
• Development and optimization of macrocyclic analogues targeting PMX.
• In vitro assays for inhibitory potency, microsomal stability, and parasite growth inhibition.
• In vivo efficacy studies in humanized mice.

Main Results:

• A lead macrocyclic compound demonstrated a 10-fold increase in PMX inhibitory potency and improved microsomal stability.
• The lead compound exhibited superior in vitro parasite growth inhibition.
• Inhibitor 7k effectively cleared blood-stage P. falciparum in mice after oral administration.

Conclusions:

• Macrocyclic analogues represent a promising class of PMX inhibitors.
• Lead compound 7k is a potent, orally bioavailable antimalarial candidate for further development.
• Targeting PMX offers a viable strategy for new antimalarial drug discovery.