Enhanced antimalarial activity of plasmepsin V inhibitors by modification of the P 2 position of PEXEL peptidomimetics

• Published in: European journal of medicinal chemistry 2018-06, Vol.154, p.182-198
• Main Authors: Nguyen, William, Hodder, Anthony N, de Lezongard, Richard Bestel, Czabotar, Peter E, Jarman, Kate E, O'Neill, Matthew T, Thompson, Jennifer K, Jousset Sabroux, Helene, Cowman, Alan F, Boddey, Justin A, Sleebs, Brad E
• Format: Article
• Language: English
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.05.022

Plasmepsin V is an aspartyl protease that plays a critical role in the export of proteins bearing the Plasmodium export element (PEXEL) motif (RxLxQ/E/D) to the infected host erythrocyte, and thus the survival of the malaria parasite. Previously, development of transition state PEXEL mimetic inhibitors of plasmepsin V have primarily focused on demonstrating the importance of the P Arg and P Leu in binding affinity and selectivity. Here, we investigate the importance of the P position by incorporating both natural and non-natural amino acids into this position and show disubstituted beta-carbon amino acids convey the greatest potency. Consequently, we show analogues with either cyclohexylglycine or phenylglycine in the P position are the most potent inhibitors of plasmepsin V that impair processing of the PEXEL motif in exported proteins resulting in death of P. falciparum asexual stage parasites.