Reexamining hydroxamate inhibitors of botulinum neurotoxin serotype A: Extending towards the β-exosite
Reexamining hydroxamate inhibitors of botulinum neurotoxin serotype A: Extending towards the β-exosite
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DOI：
10.1016/j.bmcl.2012.04.019
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发表时间：
2012-06-01
影响因子：
2.7
通讯作者：
Dickerson, Tobin J.
中科院分区：
文献类型：
--
作者：
Smith, Garry R.;Caglic, Dejan;Dickerson, Tobin J.
肉毒杆菌神经毒素(BoNTs)是人类已知的毒性最强的蛋白质，接触到它会导致迟缓性瘫痪。鉴于它们的极端效力，这些蛋白质已被研究为可能的生物恐怖主义武器；然而，在中毒后发挥作用的有效治疗方法尚未进入临床。在这里，我们重新检查了最有效的抑制剂之一，2，4-二氯肉桂基羟基甲酸酯，在已知的BONT/A轻链金属蛋白酶的可塑性的背景下。我们的研究表明，对这种化合物的修饰是可以容忍的，并会产生更好的缓蚀剂，最好的化合物的IC50为0.23微米。鉴于在类似化合物中观察到的构效关系趋势不一致，此数据建议在结构系列(C)2012 Elsevier Ltd.中进行外推时谨慎行事。保留所有权利。
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 mu M. Given the inconsistency of structure-activity relationship trends observed across similar compounds, this data argues for caution in extrapolating across structural series (C) 2012 Elsevier Ltd. All rights reserved.