Toward the discovery of dual inhibitors for botulinum neurotoxin A: concomitant targeting of endocytosis and light chain protease activity

Chem Commun (Camb). 2015 Apr 11;51(28):6226-9. doi: 10.1039/c5cc00677e.

Abstract

Dyngo-4a™ has been found to be an endocytic inhibitor of BoNT/A neurotoxicity through dynamin inhibition. Herein, we demonstrate this molecule to have a previously unrecognized dual activity against BoNT/A, dynamin-protease inhibition. To establish the importance of this dual activity, detailed kinetic analysis of Dyngo-4a's inhibition of BoNT/A metalloprotease as well as cellular and animal toxicity studies have been described. The research presented is the first polypharmacological approach to counteract BoNT/A intoxication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Botulinum Toxins, Type A / antagonists & inhibitors*
  • Botulinum Toxins, Type A / metabolism
  • Botulinum Toxins, Type A / toxicity
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Dynamins / antagonists & inhibitors*
  • Dynamins / metabolism
  • Endocytosis / drug effects*
  • Humans
  • Hydrazones / chemical synthesis
  • Hydrazones / chemistry
  • Hydrazones / pharmacology*
  • Metalloproteases / antagonists & inhibitors*
  • Metalloproteases / metabolism
  • Metalloproteases / toxicity
  • Mice
  • Molecular Structure
  • Naphthols / chemical synthesis
  • Naphthols / chemistry
  • Naphthols / pharmacology*
  • Neurons / drug effects
  • Structure-Activity Relationship
  • Toxicity Tests

Substances

  • Hydrazones
  • Naphthols
  • dyngo-4a
  • Metalloproteases
  • Botulinum Toxins, Type A
  • Dynamins