Deconvolution of the On-Target Activity of Plasmepsin V Peptidomimetics in Plasmodium falciparum Parasites
Issued Date
2025-12-12
Resource Type
eISSN
23738227
Scopus ID
2-s2.0-105024704523
Pubmed ID
41329554
Journal Title
ACS Infectious Diseases
Volume
11
Issue
12
Start Page
3581
End Page
3594
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Infectious Diseases Vol.11 No.12 (2025) , 3581-3594
Suggested Citation
Su W., Nguyen W., Siddiqui G., Dziekan J.M., Marapana D., Penington J.S., Mehra S., Razook Z., McCann K., Ngo A., Jarman K.E., Barry A.E., Papenfuss A.T., Gilson P.R., Creek D.J., Cowman A.F., Sleebs B.E., Dans M.G. Deconvolution of the On-Target Activity of Plasmepsin V Peptidomimetics in Plasmodium falciparum Parasites. ACS Infectious Diseases Vol.11 No.12 (2025) , 3581-3594. 3594. doi:10.1021/acsinfecdis.5c00742 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/113600
Title
Deconvolution of the On-Target Activity of Plasmepsin V Peptidomimetics in Plasmodium falciparum Parasites
Corresponding Author(s)
Other Contributor(s)
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.