LaMonte Gregory M, Almaliti Jehad, Bibo-Verdugo Betsaida, Keller Lena, Zou Bing Yu, Yang Jennifer, Antonova-Koch Yevgeniya, Orjuela-Sanchez Pamela, Boyle Colleen A, Vigil Edgar, Wang Lawrence, Goldgof Gregory M, Gerwick Lena, O'Donoghue Anthony J, Winzeler Elizabeth A, Gerwick William H, Ottilie Sabine
Department of Pediatrics, School of Medicine, University of California, San Diego , La Jolla, California 92093, United States.
Scripps Institution of Oceanography, University of California, San Diego , La Jolla, California 92093, United States.
J Med Chem. 2017 Aug 10;60(15):6721-6732. doi: 10.1021/acs.jmedchem.7b00671. Epub 2017 Jul 25.
Naturally derived chemical compounds are the foundation of much of our pharmacopeia, especially in antiproliferative and anti-infective drug classes. Here, we report that a naturally derived molecule called carmaphycin B is a potent inhibitor against both the asexual and sexual blood stages of malaria infection. Using a combination of in silico molecular docking and in vitro directed evolution in a well-characterized drug-sensitive yeast model, we determined that these compounds target the β5 subunit of the proteasome. These studies were validated using in vitro inhibition assays with proteasomes isolated from Plasmodium falciparum. As carmaphycin B is toxic to mammalian cells, we synthesized a series of chemical analogs that reduce host cell toxicity while maintaining blood-stage and gametocytocidal antimalarial activity and proteasome inhibition. This study describes a promising new class of antimalarial compound based on the carmaphycin B scaffold, as well as several chemical structural features that serve to enhance antimalarial specificity.
天然衍生的化合物是我们许多药典的基础，尤其是在抗增殖和抗感染药物类别中。在此，我们报告一种名为卡马霉素B的天然衍生分子是疟疾感染无性和有性血液阶段的有效抑制剂。通过在特征明确的药物敏感酵母模型中结合计算机辅助分子对接和体外定向进化，我们确定这些化合物靶向蛋白酶体的β5亚基。这些研究通过使用从恶性疟原虫分离的蛋白酶体进行体外抑制试验得到验证。由于卡马霉素B对哺乳动物细胞有毒，我们合成了一系列化学类似物，这些类似物在保持血液阶段和杀配子体抗疟活性以及蛋白酶体抑制作用的同时降低了宿主细胞毒性。本研究描述了一类基于卡马霉素B支架的有前景的新型抗疟化合物，以及几种有助于增强抗疟特异性的化学结构特征。
