Transition State Mimetics of the Plasmodium Export Element Are Potent Inhibitors of Plasmepsin V from P. falciparum and P. vivax
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- 作者：Brad E. Sleebs ; Michelle Gazdik ; Matthew T. O鈥橬eill ; Pravin Rajasekaran ; Sash Lopaticki ; Kurt Lackovic ; Kym Lowes ; Brian J. Smith ; Alan F. Cowman ; Justin A. Boddey
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：September 25, 2014
- 年：2014
- 卷：57
- 期：18
- 页码：7644-7662
- 全文大小：708K
- ISSN：1520-4804
文摘
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鈫搙E/Q/D) in the parasite鈥檚 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 P1 Leu and P3 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.