Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors
Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors
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DOI：
10.1038/s41586-020-2223-y
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发表时间：
2020-04-09
期刊：
影响因子：
64.8
通讯作者：
Yang, Haitao
中科院分区：
文献类型：
--
作者：
Jin, Zhenming;Du, Xiaoyu;Yang, Haitao
一个结构辅助药物设计和高通量筛选的项目鉴定了六种抑制SARS-CoV-2主要蛋白酶的化合物，证明了这种策略分离具有临床潜力的药物先导的能力。（SARS-CoV-2）是导致2019-2020年冠状病毒病（COVID-19）病毒性肺炎爆发的病原体（1-4）。目前，没有靶向治疗药物用于治疗这种疾病，有效的治疗选择仍然非常有限。在这里，我们描述的结果，旨在快速发现先导化合物的临床使用，结合结构辅助药物设计，虚拟药物筛选和高通量筛选的程序。该项目的重点是确定靶向SARS-CoV-2的主要蛋白酶（M-pro）的药物先导物：M-pro是冠状病毒的关键酶，在介导病毒复制和转录方面具有关键作用，使其成为SARS-CoV-2的有吸引力的药物靶标（5，6）。我们通过计算机辅助药物设计鉴定了一种基于机制的抑制剂（N3），并确定了与该化合物复合的SARS-CoV-2的M-pro的晶体结构。通过结合基于结构的虚拟和高通量筛选，我们分析了超过10，000种化合物-包括批准的药物，临床试验中的候选药物和其他具有生物活性的化合物-作为M-pro的抑制剂。这些化合物中有六种抑制M-pro，显示出半最大抑制浓度值范围为0.67至21.4 μ M。这些化合物之一（依布硒啉）也表现出有前途的抗病毒活性，在基于细胞的测定。我们的研究结果证明了我们的筛选策略的有效性，这可以导致快速发现具有临床潜力的药物线索，以应对没有特定药物或疫苗的新传染病。
A programme of structure-assisted drug design and high-throughput screening identifies six compounds that inhibit the main protease of SARS-CoV-2, demonstrating the ability of this strategy to isolate drug leads with clinical potential.A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)(1-4). Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (M-pro) of SARS-CoV-2: M-pro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2(5,6). We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of M-pro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of M-pro. Six of these compounds inhibited M-pro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 mu M. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.