Reexamining hydroxamate inhibitors of botulinum neurotoxin serotype A: Extending towards the 尾-exosite

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• 作者：Garry R. Smith^a ; Dejan Cagli膷^b ; Petr 膶apek^b ; Yan Zhang^a ; Sujata Godbole^b ; Allen B. Reitz^a ; Tobin J. Dickerson^b ; ^{tobin@scripps.edu}
• 关键词：Botulinum neurotoxin ; Hydroxamic acids ; Bioterrorism ; Rational inhibitor design
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 June, 2012
• 卷：22
• 期：11
• 页码：3754-3757
• 文件大小：3178 K

摘要

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 IC₅₀ of 0.23 渭M. Given the inconsistency of structure-activity relationship trends observed across similar compounds, this data argues for caution in extrapolating across structural series