PDF(Pubmed)
Abstract：
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation-mediated innate immune responses. Three high-throughput screening hits had the same 2-amide-3-methylester thiophene scaffold. We studied the compound binding mode using X-ray crystallography, allowing us to design analogues. Compound 27 (MDOLL-0229) had an IC50 of 2.1 μM and was selective for CoV Mac1 proteins after profiling for activity against a panel of viral and human proteins. The improved potency allowed testing of its effect on virus replication, and indeed, 27 inhibited replication of both murine hepatitis virus (MHV) prototypes CoV and SARS-CoV-2. Sequencing of a drug-resistant MHV identified mutations in Mac1, further demonstrating the specificity of 27. Compound 27 is the first Mac1-targeted small molecule demonstrated to inhibit coronavirus replication in a cell model.
摘要：
由严重急性呼吸道综合症冠状病毒2（SARS-CoV-2）病毒引起的COVID-19大流行表明，需要进一步开发抗病毒疗法。这里,我们描述了SARS-CoV-2Mac1的小分子抑制剂,其对抗ADP-核糖基化介导的先天免疫应答.三个高通量筛选命中具有相同的2-酰胺-3-甲酯噻吩支架。我们使用X射线晶体学研究了化合物结合模式，允许我们设计类似物。化合物27(MDOLL-0229)具有2.1μM的IC50,并且在针对一组病毒和人蛋白的活性进行分析后对CoVMac1蛋白具有选择性。改进的效力允许测试其对病毒复制的影响，事实上，图27抑制了鼠肝炎病毒(MHV)原型CoV和SARS-CoV-2的复制。耐药性MHV的测序鉴定了Mac1中的突变，进一步证明了27的特异性。化合物27是第一个被证明在细胞模型中抑制冠状病毒复制的Mac1靶向小分子。
