Deconstruction of Aspartic Protease Inhibitors Enables Fragment-Based Discovery of Plasmepsin V Inhibitors

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Malaria remains a significant global health challenge, with increasing resistance to current antimalarial drugs necessitating novel therapeutic approaches.
• Plasmepsin V (PMV), a Plasmodium aspartic protease crucial for parasite survival, presents a promising drug target due to its structural divergence from human proteases, enabling selective inhibition.

Purpose of the Study:

• To identify and optimize non-peptidomimetic inhibitors of Plasmepsin V (PMV) with potential as new antimalarial agents.
• To explore structure-activity relationships (SAR) for PMV inhibitors based on fragment-inspired scaffolds.

Main Methods:

• A structure-informed, deconstruction-based approach was used to mine PMV inhibitor motifs.
• A focused fragment-like library was synthesized and screened using a FRET-based assay.
• Structure-activity relationship studies guided optimization of lead compounds, including SAR exploration around pyrrolidine scaffolds.

Main Results:

• Fragment-inspired compounds based on pyrrolidine, piperidine, and piperazine cores demonstrated measurable PMV inhibition.
• A trans-3,4-disubstituted pyrrolidine derivative (7a) showed initial activity (IC50 70 µM) and was selected for optimization.
• Optimization led to N-sulfonamide analogs with improved potency in the low micromolar range (~10 µM), featuring specific aromatic substitutions.

Conclusions:

• A promising non-peptidomimetic scaffold targeting Plasmepsin V was established.
• The identified compounds represent a viable starting point for developing selective PMV inhibitors as novel antimalarial drugs.
• This study highlights the potential of structure-informed fragment-based approaches for discovering new antimalarial therapies.