期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 18, 页码 7644-7662出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm500797g
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资金
- National Health and Medical Research Council of Australia [1010326]
- Human Frontiers Science Program [RGY0073/2012]
- Ramaciotti Foundation [3197/2010]
- CASS Foundation Science and Medicine [SM.12.4348]
- Australian Cancer Research Foundation
- Victorian State Government Operational Infrastructure Support
- Australian Government NHMRC IRIISS
- University of Melbourne
Following erythrocyte invasion, malaria parasites export a catalogue of remodeling proteins into the infected cell that enable parasite development in the human host. Export is dependent on the activity of the aspartyl protease, plasmepsin V (PMV), which cleaves proteins within the Plasmodium export element (PEXEL; RxL down arrow xE/Q/D) in the parasite's endoplasmic reticulum. Here, we generated transition state mimetics of the native PEXEL substrate that potently inhibit PMV isolated from Plasmodium falciparum and Plasmodium vivax. Through optimization, we identified that the activity of the mimetics was completely dependent on the presence of P-1 Leu and P-3 Arg. Treatment of P. falciparum-infected erythrocytes with a set of optimized mimetics impaired PEXEL processing and killed the parasites. The striking effect of the compounds provides a clearer understanding of the accessibility of the PMV active site and reaffirms the enzyme as an attractive target for the design of future antimalarials.
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