期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 8, 页码 2933-2943出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm200022g
关键词
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资金
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
- NIH, Center for Cancer Research
- NCI-Frederick
- National Cancer Institute, National Institutes of Health
- Joint Science and Technology Office of the Department of Defense
Our current study reports the first K(M) optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K(M) = 80 mu M) was converted from a subs trate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid, and by attachment of an aminooxy handle for further structural optimization by mime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequenly employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC(50) = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition Of intracellular Y pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.
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