Beijing Center for Disease Control and Prevention, Beijing 100013, PR China.
BMB Rep. 2011 Dec;44(12):811-5. doi: 10.5483/bmbrep.2011.44.12.811.
Inhalational anthrax is caused by B. anthracis, a virulent sporeforming bacterium which secretes anthrax toxins consisting of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease and is the main determinant in the pathogenesis of anthrax. Here we report the identification of a lead small-molecule inhibitor of anthrax lethal factor by screening an available synthetic small-molecule inhibitor library using fluorescence-based high-throughput screening (HTS) approach. Seven small molecules were found to have inhibitory effect against LF activity, among which SM157 had the highest inhibitory activity. All theses small molecule inhibitors inhibited LF in a noncompetitive inhibition mode. SM157 and SM167 are from the same family, both having an identical group complex, which is predicted to insert into S1' pocket of LF. More potent small-molecule inhibitors could be developed by modifying SM157 based on this identical group complex.
吸入性炭疽是由炭疽杆菌引起的，炭疽杆菌是一种产生孢子的毒力细菌，它分泌炭疽毒素，由保护性抗原（PA）、致死因子（LF）和水肿因子（EF）组成。LF 是一种 Zn 依赖性金属蛋白酶，是炭疽病发病机制的主要决定因素。在这里，我们通过使用基于荧光的高通量筛选（HTS）方法筛选现有的合成小分子抑制剂文库，鉴定出炭疽致死因子的先导小分子抑制剂。发现有 7 种小分子对 LF 活性具有抑制作用，其中 SM157 具有最高的抑制活性。所有这些小分子抑制剂均以非竞争性抑制模式抑制 LF。SM157 和 SM167 来自同一家族，都具有相同的基团复合物，预计该复合物将插入 LF 的 S1'口袋。通过基于该相同基团复合物修饰 SM157，可以开发出更有效的小分子抑制剂。
