Targeting Bacterial Sortase A with Covalent Inhibitors: 27 New Starting Points for Structure-Based Hit-to-Lead Optimization
Targeting Bacterial Sortase A with Covalent Inhibitors: 27 New Starting Points for Structure-Based Hit-to-Lead Optimization
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DOI：
10.1021/acsinfecdis.9b00265
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发表时间：
2020-02-01
影响因子：
5.3
通讯作者：
Leonchiks, Ainars
中科院分区：
文献类型：
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作者：
Jaudzems, Kristaps;Kurbatska, Viktorija;Leonchiks, Ainars
由于其作为细菌毒力因子的重要作用，酶分选酶A（SrtA）已成为开发针对革兰氏阳性菌感染的新的抗毒力药物的有吸引力的靶标。在这里，我们描述了27种化合物鉴定为共价抑制剂的金黄色葡萄球菌SrtA的筛选库约50 000化合物使用FRET测定，然后由NMR为基础的验证和结合可逆性分析。这些化合物中有19种仅显示出中等至弱的细胞毒性，对NIH 3 T3小鼠成纤维细胞的CC 50范围为12至740 μ M。使用共价对接的分析表明，抑制剂最初通过疏水相互作用，随后通过SrtA活性位点半胱氨酸和亲电子中心的抑制剂之间的共价键形成。所述化合物代表了良好的起点，其具有开发成广谱抗病毒剂的潜力，如通过所述化合物之一的命中-先导优化所例示的。
Because of its essential role as a bacterial virulence factor, enzyme sortase A (SrtA) has become an attractive target for the development of new antivirulence drugs against Gram-positive infections. Here we describe 27 compounds identified as covalent inhibitors of Staphylococcus aureus SrtA by screening a library of approximately 50 000 compounds using a FRET assay followed by NMR-based validation and binding reversibility analysis. Nineteen of these compounds displayed only moderate to weak cytotoxicity, with CC50 against NIH 3T3 mice fibroblast cells ranging from 12 to 740 mu M. Analysis using covalent docking suggests that the inhibitors initially associate via hydrophobic interactions, followed by covalent bond formation between the SrtA active site cysteine and an electrophilic center of the inhibitor. The compounds represent good starting points that have the potential to be developed into broad spectrum antivirulence agents as exemplified by hit-to-lead optimization of one of the compounds.