Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen.
Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen.
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DOI：
10.1021/acsptsci.0c00216
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发表时间：
2021-06-11
影响因子：
--
通讯作者：
Zaliani A
中科院分区：
文献类型：
--
作者：
Kuzikov M;Costanzi E;Reinshagen J;Esposito F;Vangeel L;Wolf M;Ellinger B;Claussen C;Geisslinger G;Corona A;Iaconis D;Talarico C;Manelfi C;Cannalire R;Rossetti G;Gossen J;Albani S;Musiani F;Herzog K;Ye Y;Giabbai B;Demitri N;Jochmans D;Jonghe S;Rymenants J;Summa V;Tramontano E;Beccari AR;Leyssen P;Storici P;Neyts J;Gribbon P;Zaliani A
化合物再利用是确定针对SARS-CoV-2感染和COVID-19疾病的有效治疗方案的重要策略。在这方面，SARS-CoV-2主要蛋白酶（3CL-Pro），也称为M-Pro，是一个有吸引力的药物靶点，因为它通过在多个不同的切割位点加工病毒多聚蛋白pp 1a和pp 1ab在病毒复制中发挥核心作用。我们在这里报告了一个再利用计划的结果，该计划涉及8.7 K含有市售药物、临床和临床前候选药物以及被认为对人体安全的小分子化合物。我们证实了先前报道的3CL-Pro抑制剂，并鉴定了62种IC 50值低于1 μM的其他化合物，并分析了它们对中东呼吸综合征病毒糜蛋白酶和3CL-Pro的选择性。八种抑制剂的子集在Vero-E6细胞系中显示出抗细胞病变作用，并分析了化合物硫代鸟苷和MG-132与SARS-CoV-2 3CL-Pro的预测结合特征。杨梅素和SARS-Cov-2 3CL-Pro的复合物的X射线晶体结构在1.77 nm的分辨率下解析，表明杨梅素与催化Cys 145共价结合，因此抑制其酶活性。
Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro and have identified 62 additional compounds with IC50 values below 1 μM and profiled their selectivity toward chymotrypsin and 3CL-Pro from the Middle East respiratory syndrome virus. A subset of eight inhibitors showed anticytopathic effect in a Vero-E6 cell line, and the compounds thioguanosine and MG-132 were analyzed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.
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影响因子：
1.7
作者：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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通讯作者：
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