Synthesis and evaluation of library of betulin derivatives against the botulinum neurotoxin A protease

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2229-31. doi: 10.1016/j.bmcl.2011.02.115. Epub 2011 Mar 4.

Abstract

Botulinum neurotoxins (BoNTs) are the most toxic proteins currently known. Current treatments for botulinum poisoning are all protein based with a limited window of opportunity. Inhibition of the BoNT light chain protease (LC) has emerged as a new therapeutic strategy for the treatment of botulism as it may provide an effective post-exposure remedy. As such, a small library of 40 betulin derivatives was synthesized and screened against the light chain of BoNT serotype A (LC/A); five positive hits (IC(50) <100 μM) were uncovered. Detailed evaluation of inhibition mechanism of three most active compounds revealed a competitive model, with sub-micromolar K(i) value for the best inhibitor (7). Unfortunately, an in vitro cell-based assay did not show any protection of rat cerebellar neurons against BoNT/A intoxication by 7.

Publication types

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

MeSH terms

  • Animals
  • Botulinum Toxins / chemical synthesis
  • Botulinum Toxins / chemistry*
  • Botulinum Toxins / pharmacology
  • Botulinum Toxins, Type A / antagonists & inhibitors*
  • Botulinum Toxins, Type A / metabolism
  • Neurons / drug effects
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Rats
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Succinates / chemical synthesis*
  • Succinates / chemistry
  • Succinates / pharmacology
  • Triterpenes / chemical synthesis*
  • Triterpenes / chemistry
  • Triterpenes / pharmacology

Substances

  • Protease Inhibitors
  • Small Molecule Libraries
  • Succinates
  • Triterpenes
  • Botulinum Toxins
  • Botulinum Toxins, Type A