Deconvolution of the On-Target Activity of Plasmepsin V Peptidomimetics in Plasmodium falciparum Parasites

Su, W; Nguyen, W; Siddiqui, G; Dziekan, JM; Marapana, D; Penington, JS; Mehra, S; Razook, Z; McCann, K; Ngo, A; Jarman, KE; Barry, AE; Papenfuss, AT; Gilson, PR; Creek, DJ; Cowman, AF; Sleebs, BE; Dans, MG

Author(s): Su, W; Nguyen, W; Siddiqui, G; Dziekan, JM; Marapana, D; Penington, JS; Mehra, S; Razook, Z; McCann, K; Ngo, A; Jarman, KE; Barry, AE; Papenfuss, AT; Gilson, PR; Creek, DJ; Cowman, AF; Sleebs, BE; Dans, MG;
Details: Publication Year 2025-12-12,Volume 11,Issue #12,Page 3581-3594
Journal Title: ACS Infectious Diseases
Abstract: Plasmepsin V (PMV), an essential aspartyl protease, plays a critical role during the asexual blood stage of infection of Plasmodium by enabling the export of parasite proteins into the host red blood cell. This export is vital for parasite survival and pathogenesis, making PMV an attractive target for antimalarial drug development. Peptidomimetic inhibitors designed to mimic the natural substrate of PMV have demonstrated potent parasite-killing activity by blocking protein export. While these compounds have been instrumental in validating PMV as a bona fide antimalarial target, inconsistencies between their biochemical potency and cellular activity have raised questions regarding their precise mechanism of action. In this study, we employed chemoproteomic approaches, including solvent-induced protein precipitation and intact-cell thermal profiling, to demonstrate PMV target engagement by the peptidomimetics. To further support these findings, we generated parasite lines exhibiting reduced sensitivity to peptidomimetics. Through whole-genome sequencing of these parasite lines, a single nucleotide variant within the pmv gene was revealed. This mutation was later validated using reverse genetics, confirming its role in mediating resistance. Together, these data provide strong evidence that the peptidomimetics exert their antimalarial activity by directly targeting PMV. These findings further support the potential of PMV as a validated and promising target for future antimalarial drug development.
Publisher: ACS
Keywords: *Plasmodium falciparum/drug effects/genetics/enzymology; *Peptidomimetics/pharmacology/chemistry; *Aspartic Acid Endopeptidases/antagonists & inhibitors/genetics/metabolism; *Antimalarials/pharmacology/chemistry; Humans; *Protozoan Proteins/genetics/antagonists & inhibitors/metabolism; Malaria, Falciparum/parasitology/drug therapy; Plasmodium; antimalarial; aspartyl protease; malaria; plasmepsin
Research Division(s): New Medicines and Diagnostics; Infection and Global Health; Bioinformatics and Computational Biology
PubMed ID: 41329554
Publisher's Version: https://doi.org/10.1021/acsinfecdis.5c00742
Open Access at Publisher's Site: https://doi.org/10.1021/acsinfecdis.5c00742
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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