Novel Small-Molecule Antibacterial Agents

Abstract

The specific aim of this proposal is to develop improved small-molecule botulinum neurotoxin serotype A endopeptidase (BoNTAe) inhibitors with Ki values of <100 nM. We have developed BoNTAe inhibitors MHC and HAB (see US Patent 8,404,728 B2) that showed significant 6-hour-post-exposure protection of mice against 5 LD50 BoNTA. HAB also showed significant 4-hour-post-exposure protection of zebrafish against 5 LD50 BoNTA. Our kinetics and affinity analyses using the surface plasmon resonance technique showed that the Ki value of our BoNTAe inhibitor AHP (see US Patent 8,404,728 B2) is 71 + or - 26 nM (2 independent experiments with chi square values of 0.393 and 0.396). In addition, we have developed a generic approach to cysteine-targeting irreversible inhibitors of pathogenic enzymes (Adv. Insect Physiol. 46, 435-494, 2014) that enables conversion of our reversible BoNTAe inhibitors to irreversible inhibitors that target Cys164 in the BoNTAe active site to effectively counteract BoNTA that has an unusually long in vivo half life of ~31 days.

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Document Details

Document Type
Technical Report
Publication Date
Jul 01, 2014
Accession Number
ADA612221

Entities

People

  • Yuan-Ping Pang

Organizations

  • Mayo Clinic

Tags

Communities of Interest

  • Human Systems

DTIC Thesaurus Topics

  • Abstracts
  • Agreements
  • Anti-Bacterial Agents
  • Department Of Defense
  • Education
  • Engineering
  • Information Operations
  • Inhibitors
  • Molecules
  • Neurotoxins
  • Patents
  • Resonance
  • Small Molecules
  • Students
  • Surface Plasmon Resonance
  • Surface Plasmons
  • Technology Transfer

Fields of Study

  • Medicine

Readers

  • Analytical Mechanics
  • Materials Science and Engineering.
  • Molecular and Cellular Biochemistry