Reexamining hydroxamate inhibitors of botulinum neurotoxin serotype A: Extending towards the beta-exosite.
Publication Year:
2012
PubMed ID:
22542019
Funding Grants:
Public Summary:
Botulinum neurotoxins (BoNTs) are the most toxic proteins known to man, exposure to which results in characteristic flaccid paralysis. Given their extreme potency (the lethal dose for a 70 kg person is approximately 70 ng of toxin), 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 small molecule 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 IC50 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.
Scientific Abstract:
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 0.23muM. Given the inconsistency of structure-activity relationship trends observed across similar compounds, this data argues for caution in extrapolating across structural series.