Mechanism of inhibition of botulinum neurotoxin type A light chain by two quinolinol compounds

Yacoba V.T. Minnow, Ronald Goldberg, Sreedhar R. Tummalapalli, David P. Rotella, Nina M. Goodey

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Quinolinol-based compounds are a promising starting point for discovery of effective inhibitors of the clostridial neurotoxin, botulinum neurotoxin type A light chain (BoNT/A LC). Insights into the mechanism of inhibition by quinolinol compounds facilitate interpretation of docking data and inhibitor optimization. In this study, a fluorogenic substrate of BoNT/A, SNAPtide, was used to study the mechanism by which two new quinolinol compounds, MSU58 and MSU84, with IC50 values of 3.3 μM and 5.8 μM, respectively, inhibit BoNT/A LC. Kinetic studies and model discrimination analysis showed both compounds to be competitive inhibitors of BoNT/A LC with inhibition constants (KI) 3.2 μM and 6.2 μM for MSU58 and MSU84, respectively. These data indicate that the inhibitors bind in the BoNT/A LC active site and that inhibitor binding is mutually exclusive with the binding of the substrate. This is the first study to report the competitive inhibition of BoNT/A LC by quinolinol compounds. These data help define the inhibitor binding pocket and, along with structure activity relationship studies, provide immediate direction for further compound synthesis.

Original languageEnglish
Pages (from-to)15-22
Number of pages8
JournalArchives of Biochemistry and Biophysics
Volume618
DOIs
StatePublished - 15 Mar 2017

Keywords

  • Botulinum
  • Competitive inhibitor
  • FRET peptide
  • Fluorescence quenching
  • Neurotoxin
  • Quinolinol

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