Microbiotix Inc, One Innovation Drive, Worcester, Massachusetts 01605, USA.
J Med Chem. 2010 Mar 11;53(5):2264-76. doi: 10.1021/jm901852f.
NSC 240898 was previously identified as a botulinum neurotoxin A light chain (BoNT/A LC) endopeptidase inhibitor by screening the National Cancer Institute Open Repository diversity set. Two types of analogues have been synthesized and shown to inhibit BoNT/A LC in a FRET-based enzyme assay, with confirmation in an HPLC-based assay. These two series of compounds have also been evaluated for inhibition of anthrax lethal factor (LF), an unrelated metalloprotease, to examine enzyme specificity of the BoNT/A LC inhibition. The most potent inhibitor against BoNT/A LC in these two series is compound 12 (IC(50) = 2.5 microM, FRET assay), which is 4.4-fold more potent than the lead structure and 11.2-fold more selective for BoNT/A LC versus the anthrax LF metalloproteinase. Structure-activity relationship studies have revealed structural features important to potency and enzyme specificity.
NSC 240898 先前通过筛选国立癌症研究所开放存储库多样性集被鉴定为肉毒神经毒素 A 轻链 (BoNT/A LC) 内切酶抑制剂。已经合成了两种类似物，并在基于荧光各向异性的酶测定中显示出对 BoNT/A LC 的抑制作用，在基于 HPLC 的测定中得到了证实。这两个系列的化合物也已被评估用于抑制炭疽致死因子 (LF)，一种无关的金属蛋白酶，以检查 BoNT/A LC 抑制的酶特异性。这两个系列中对 BoNT/A LC 抑制作用最强的抑制剂是化合物 12（IC（50）= 2.5 microM，FRET 测定），其对 BoNT/A LC 的效力比先导结构高 4.4 倍，对炭疽 LF 金属蛋白酶的选择性高 11.2 倍。构效关系研究揭示了对效力和酶特异性重要的结构特征。
