Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity
Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity
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DOI：
10.1016/j.bbrc.2003.08.112
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发表时间：
2003-10-10
影响因子：
3.1
通讯作者：
Bavari, S
中科院分区：
文献类型：
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作者：
Burnett, JC;Schmidt, JJ;Bavari, S
肉毒杆菌神经毒素（BoNTs）是已被武器化的最致命的生物物质之一，被列为生物防御A类制剂。目前，还没有小分子（非肽类）疗法可以对抗这种威胁；因此，鉴定和开发抑制bont的化合物是当务之急。在本研究中，采用高通量测定方法鉴定了抑制BoNT血清型a轻链（BoNT/ a LC）金属蛋白酶活性的小分子。所有抑制剂都使用基于高效液相色谱的分析进一步验证。这些化合物的构象分析，结合分子对接研究，用于预测有助于抑制剂结合和效力的结构特征。基于这些结果，提出了BoNT/ a LC抑制剂的共同药效团。这是首次报道小分子（非肽）在低muM范围内抑制BoNT/A LC金属蛋白酶活性的研究。(C) 2003 Elsevier Inc.版权所有。
Botulinum neurotoxins (BoNTs) are among the most lethal biological substances to have been weaponized and are listed as biodefense category A agents. Currently, no small molecule (non-peptidic) therapeutics exist to counter this threat; hence, identifying and developing compounds that inhibit BoNTs is a high priority. In the present study, a high-throughput assay was used to identify small molecules that inhibit the metalloprotease activity of BoNT serotype A light chain (BoNT/A LC). All inhibitors were further verified using a HPLC-based assay. Conformational analyses of these compounds, in conjunction with molecular docking studies, were used to predict structural features that contribute to inhibitor binding and potency. Based on these results, a common pharmacophore for BoNT/A LC inhibitors is proposed. This is the first study to report small molecules (non-peptidics) that inhibit BoNT/A LC metalloprotease activity in the low muM range. (C) 2003 Elsevier Inc. All rights reserved.