期刊
ACS CHEMICAL BIOLOGY
卷 12, 期 2, 页码 422-434出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.6b01037
关键词
-
资金
- Bill and Melinda Gates Foundation
- Grand Challenge in Global Health Exploration Grant [OPP1086217, OPP1141300]
- UC San Diego Medical Scientist Training Program [T32 GM007198-40]
- DoD National Defense Science and Engineering Fellowship Program
- NIH [5R01AI090141, R01AI103058, UL1TR000100, AI095437]
- National Biomedical Computation Resource (NBCR) [NIH P41 GM103426]
- New Innovator Award [NIH DP2 OD007237]
- Canadian Institutes of Health Research [338511]
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]
Recent advances in cell-based, high-throughput phenotypic screening have identified new chemical compounds that are active against eukaryotic pathogens. A challenge to their future development lies in identifying these compounds molecular targets and binding modes. In particular, subsequent structure-based chemical optimization and target-based screening require a detailed understanding of the binding event. Here, we use directed evolution and whole-genome sequencing of a drug-sensitive S. cerevisiae strain to identify the yeast ortholog of TcCyp51, lanosterol-14-alpha-demethylase (TcCyp51), as the target of MMV001239, a benzamide compound with activity against Trypanosoma cruzi, the etiological agent of Chagas disease. We show that parasites treated with MMV0001239 phenocopy parasites treated with another TcCyp51 inhibitor, posaconazole, accumulating both lanosterol and eburicol. Direct drugprotein binding of MMV0001239 was confirmed through spectrophotometric binding assays and X-ray crystallography, revealing a binding site shared with other antitrypanosomal compounds that target Cyp51. These studies provide a new probe chemotype for TcCyp51 inhibition.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据