Quinolinol and Peptide Inhibitors of Zinc Protease in Botulinum Neurotoxin A: Effects of Zinc Ion and Peptides on Inhibition

Abstract

Quinolinol derivatives were found to be effective inhibitors of botulinum neurotoxin serotype A (BoNT/ A). Studies of the inhibition and binding of 7-(phenyl(8-quinolinylamino)methyl)-8-quinolinol (QAQ) to the light chain domain (BoNT/A LC) showed that QAQ is a non-competitive inhibitor for the zinc protease activity. Binding and molecular modeling studies reveal that QAQ binds to a hydrophobic pocket near the active site. Its inhibitor effect does not involve the removal of zinc ion from the light chain. A 24-mer SNAP-25 peptide containing E183 to G206 with Q197C mutation (Peptide C) binds to BoNT/A LC with an unusually slow second order binding rate constant of 76.7 M1 s1. QAQ binds to Zn2+-free BoNT/A LC with a KD of 0.67 lM and to Peptide C?BoNT/A LC complex with a KD of 2.33 lM. The insights of the interactions of quinolinols and peptides with the zinc protease of BoNT/A should aid in the development of inhibitors of metalloproteases.

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Document Details

Document Type
Technical Report
Publication Date
Jan 01, 2009
Accession Number
ADA513589

Entities

People

  • David C. Yang
  • Huiguo Lai
  • Leonard A. Smith
  • Mang Feng
  • Sivanesan Dakshanamurthy
  • Virginia Roxas-duncan

Organizations

  • United States Army Medical Research Institute of Infectious Diseases

Tags

DTIC Thesaurus Topics

  • Amino Acids
  • Biochemistry
  • Biophysics
  • Chemical Compounds
  • Chemical Kinetics
  • Chemical Synthesis
  • Chemistry
  • Density Functional Theory
  • Dissociation
  • Enzyme Inhibitors
  • Hydrophobic Properties
  • Inhibition
  • Inhibitors
  • Materials
  • Neurotoxins
  • Quantum Mechanics
  • Quinolinols

Fields of Study

  • Chemistry

Readers

  • Molecular and Cellular Biochemistry