8TYH

Plasmodium vivax PMX

Summary for 8TYH

• Entry DOI: 10.2210/pdb8tyh/pdb
• Descriptor: Aspartyl protease, putative, GLYCEROL, 6-tungstotellurate(VI), ... (5 entities in total)
• Functional Keywords: plasmepsinix, plasmepsinx, inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Plasmodium vivax Sal-1
• Total number of polymer chains: 1
• Total formula weight: 61517.46

Authors

Hodder, A.N.,Scally, S.W.,Cowman, A.F. (deposition date: 2023-08-25, release date: 2024-08-28, Last modification date: 2025-09-10)

Primary citation

Hodder, A.N.,Sleebs, B.E.,Adams, G.,Rezazadeh, S.,Ngo, A.,Jarman, K.,Scally, S.,Czabotar, P.,Wang, H.,McCauley, J.A.,Olsen, D.B.,Cowman, A.F.
Structure-activity analysis of imino-pyrimidinone-fused pyrrolidines aids the development of dual plasmepsin V and plasmepsin X inhibitors.
Febs J., 292:2843-2864, 2025

PubMed Abstract: A library of known aspartic protease inhibitors was screened to identify compounds that inhibit plasmepsin V from Plasmodium vivax. This screen revealed compounds with an imino-pyrimidinone-fused pyrrolidine (IPF) scaffold that exhibited sub-micromolar inhibitory activity against plasmepsin V. Further screening of IPF analogs against the related aspartic protease plasmepsin X showed inhibitory activity, while a third aspartic protease, plasmepsin IX, was not significantly inhibited. Modifications to the P1 biaryl region of the IPF scaffold differentially modulated inhibition of both plasmepsin V and X. Notably, analogs with potent plasmepsin X inhibitory activity successfully blocked the growth of Plasmodium falciparum in vitro. X-ray structures of IPF analogs in complex with plasmepsin V provided insights into their binding mode and revealed avenues to further improve IPF potency and selectivity between plasmepsin V and X. This understanding of how these compounds interact with the active sites of plasmepsin V and X will serve as a foundation for the future design of dual inhibitors targeting these proteases.

PubMed: 40035447
DOI: 10.1111/febs.70038

Experimental method

X-RAY DIFFRACTION (1.83 Å)