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Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase

  1. Author:
    Bahta, M.
    Lountos, G. T.
    Dyas, B.
    Kim, S. E.
    Ulrich, R. G.
    Waugh, D. S.
    Burke, T. R.

  2. Author Address

    [Bahta, M; Kim, SE; Burke, TR] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA [Lountos, GT; Waugh, DS] NCI, Macromol Crystallog Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA [Dyas, B; Ulrich, RG] USA, Lab Mol Immunol, Med Res Inst Infect Dis, Frederick, MD 21702 USA;Burke, TR (reprint author), NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA;tburke@helix.nih.gov
    1. Year: 2011
    2. Date: Apr
  2. Journal: Journal of Medicinal Chemistry
    1. 54
    2. 8
    3. Pages: 2933-2943
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    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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External Sources

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  2. DOI: 10.1021/jm200022g
  3. View record in Web of Science®
  4. WOS: 000289697800028

Library Notes

  1. Fiscal Year: FY2010-2011
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