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 P3 Arg and P1 Leu in binding affinity and selectivity. Here, we investigate the importance of the P2 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 P2 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.

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