Zwitterionic pyrrolidene-phosphonates: Inhibitors of the glycoside hydrolase-like phosphorylase: Streptomyces coelicolor GlgEI-V279S

Sri Kumar Veleti, Cecile Petit, Donald R. Ronning, Steven J. Sucheck

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

We synthesized and evaluated new zwitterionic inhibitors against glycoside hydrolase-like phosphorylase Streptomyces coelicolor (Sco) GlgEI-V279S which plays a role in α-glucan biosynthesis. Sco GlgEI-V279S serves as a model enzyme for validated anti-Tuberculosis (TB) target Mycobacterium tuberculosis (Mtb) GlgE. Pyrrolidine inhibitors 5 and 6 were designed based on transition state considerations and incorporate a phosphonate on the pyrrolidine moiety to expand the interaction network between the inhibitor and the enzyme active site. Compounds 5 and 6 inhibited Sco GlgEI-V279S with Ki = 45 ± 4 μM and 95 ± 16 μM, respectively, and crystal structures of Sco GlgE-V279S-5 and Sco GlgE-V279S-6 were obtained at a 3.2 Å and 2.5 Å resolution, respectively.

Original languageEnglish (US)
Pages (from-to)3884-3891
Number of pages8
JournalOrganic and Biomolecular Chemistry
Volume15
Issue number18
DOIs
StatePublished - Jan 1 2017

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ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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