Tripeptide inhibitors of Yersinia protein-tyrosine phosphatase

Kyeong Lee, Yang Gao, Zhu Jun Yao, Jason Phan, Li Wu, Jiao Liang, David S. Waugh, Zhong Yin Zhang, Terrence R. Burke

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The protein-tyrosine phosphatase (PTP) 'YopH' is a virulence factor of Yersinia pestis, the causative agent of plague. Potential use of Yersinia as a bioterrorism agent renders YopH inhibitors of therapeutic importance. Previously, we had examined the inhibitory potencies of a variety of phosphotyrosyl (pTyr) mimetics against the human PTP1B enzyme by displaying them in the EGFR-derived hexapeptide sequence, 'Ac-Asp-Ala-Asp-Glu-Xxx-Leu-amide', where Xxx=pTyr mimetic. The poor inhibitory potencies of certain of these pTyr mimetics were attributed to restricted orientation within the PTP1B catalytic pocket incurred by extensive peripheral interaction of the hexapeptide platform. Utilizing the smaller tripeptide platform, 'Fmoc-Glu-Xxx-Leu-amide' we demonstrate herein that several of the low affinity hexapeptide-expressed pTyr mimetics exhibit high PTP1B affinity within the context of the tripeptide platform. Of particular note, the mono-anionic 4-(carboxydifluoromethyl)Phe residue exhibits affinity equivalent to the di-anionic F2Pmp residue, which had previously been among the most potent PTP-binding motifs. Against YopH, it was found that all tripeptides having Glu residues with an unprotected side chain carboxyl were inactive. Alternatively, in their Glu-OBn ester forms, several of the tripeptides exhibited good YopH affinity with the mono-anionic peptide, Fmoc-Glu(OBn)-Xxx-Leu-amide, where Xxx=4-(carboxymethyloxy)Phe providing an IC50 value of 2.8 μM. One concern with such inhibitors is that they may potentially function by non-specific mechanisms. Studies with representative inhibitors, while failing to provide evidence of a non-specific promiscuous mode of inhibition, did indicate that non-classical inhibition may be involved.

Original languageEnglish (US)
Pages (from-to)2577-2581
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume13
Issue number15
DOIs
StatePublished - Aug 4 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Lee, K., Gao, Y., Yao, Z. J., Phan, J., Wu, L., Liang, J., Waugh, D. S., Zhang, Z. Y., & Burke, T. R. (2003). Tripeptide inhibitors of Yersinia protein-tyrosine phosphatase. Bioorganic and Medicinal Chemistry Letters, 13(15), 2577-2581. https://doi.org/10.1016/S0960-894X(03)00481-5