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Oxime-based click chemistry in the development of 3-isoxazolecarboxylic acid containing inhibitors of Yersinia pestis protein tyrosine phosphatase, YopH.

ABSTRACT: The pathogenicity of Yersinia pestis relies on several effector proteins including YopH, a protein tyrosine phosphatase (PTP). We previously screened a library of analogues based on the ubiquitous PTP substrate para-nitrophenylphosphate (pNPP) and found that incorporation of a 3-phenyl substituent to give 6-nitro-[1,1'-biphenyl]-3-yldihydrogen phosphate (1) enhanced affinity. Herein we report the conversion of 1 from a substrate into an inhibitor by replacing the hydrolysable phosphoryl group with a 3-isoxazolecarboxylic acid moiety and by introduction of an aminooxy group and subsequent diversification using oxime-based click chemistry. This approach led to the identification of non-promiscuous bidentate YopH inhibitors with affinity in the low micromolar range.

SUBMITTER: Bahta M

PROVIDER: S-EPMC3734799 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Oxime-based click chemistry in the development of 3-isoxazolecarboxylic acid containing inhibitors of Yersinia pestis protein tyrosine phosphatase, YopH.

Bahta Medhanit M Burke Terrence R TR

ChemMedChem 20110610 8

The pathogenicity of Yersinia pestis relies on several effector proteins including YopH, a protein tyrosine phosphatase (PTP). We previously screened a library of analogues based on the ubiquitous PTP substrate para-nitrophenylphosphate (pNPP) and found that incorporation of a 3-phenyl substituent to give 6-nitro-[1,1'-biphenyl]-3-yldihydrogen phosphate (1) enhanced affinity. Herein we report the conversion of 1 from a substrate into an inhibitor by replacing the hydrolysable phosphoryl group wi ...[more]

PMID: 21671403

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