Reexamining hydroxamate inhibitors of botulinum neurotoxin serotype A: extending towards the β-exosite

Bioorg Med Chem Lett. 2012 Jun 1;22(11):3754-7. doi: 10.1016/j.bmcl.2012.04.019. Epub 2012 Apr 11.


Botulinum neurotoxins (BoNTs) are the most toxic proteins known to man, exposure to which results in flaccid paralysis. Given their extreme potency, these proteins have become studied as possible weapons of bioterrorism; however, effective treatments that function after intoxication have not progressed to the clinic. Here, we have reexamined one of the most effective inhibitors, 2,4-dichlorocinnamyl hydroxamate, in the context of the known plasticity of the BoNT/A light chain metalloprotease. Our studies have shown that modifications of this compound are tolerated and result in improved inhibitors, with the best compound having an IC(50) of 0.23 μM. Given the inconsistency of structure-activity relationship trends observed across similar compounds, this data argues for caution in extrapolating across structural series.

Publication types

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

MeSH terms

  • Binding Sites
  • Botulinum Toxins, Type A / antagonists & inhibitors*
  • Botulinum Toxins, Type A / metabolism
  • Computer Simulation
  • Hydroxamic Acids / chemistry*
  • Protease Inhibitors / chemistry*
  • Protein Structure, Tertiary
  • Structure-Activity Relationship


  • Hydroxamic Acids
  • Protease Inhibitors
  • Botulinum Toxins, Type A