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

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 0.23 ?M. Given the inconsistency of structure-activity relationship trends observed across similar compounds, this data argues for caution in extrapolating across structural series.

SUBMITTER: Smith GR

PROVIDER: S-EPMC3352981 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Smith Garry R GR Caglič Dejan D Capek Petr P Zhang Yan Y Godbole Sujata S Reitz Allen B AB Dickerson Tobin J TJ

Bioorganic & medicinal chemistry letters 20120411 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. Ou ...[more]

PMID: 22542019

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