Structure-activity analysis of imino-pyrimidinone-fused pyrrolidines aids the development of dual plasmepsin V and plasmepsin X inhibitors
- Author(s)
- Hodder, AN; Sleebs, BE; Adams, G; Rezazadeh, S; Ngo, A; Jarman, K; Scally, S; Czabotar, P; Wang, H; McCauley, JA; Olsen, DB; Cowman, AF;
- Journal Title
- FEBS Journal
- Publication Type
- Mar 4
- 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.
- Publisher
- Wiley
- Keywords
- dual inhibition; imino‐pyrimidinone‐fused pyrrolidine; plasmepsin IX; plasmepsin V; plasmepsin X
- Research Division(s)
- Infection and Global Health; New Medicines and Diagnostics; Advanced Technology and Biology
- PubMed ID
- 40035447
- Publisher's Version
- https://doi.org/10.1111/febs.70038
- Open Access at Publisher's Site
https://doi.org/10.1111/febs.70038- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-05-29 02:41:28
Last Modified: 2025-05-29 02:41:49