Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2
Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2
复制标题
拟肽醛作为肠道病毒和 SARS-CoV-2 广谱抑制剂的设计、合成和生物学评价
DOI：
10.1021/acs.jmedchem.0c02258
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发表时间：
2022-02-24
影响因子：
7.3
通讯作者：
Liu, Hong
中科院分区：
文献类型：
--
作者：
Dai, Wenhao;Jochmans, Dirk;Liu, Hong
以肠道病毒71型（EV 71）3C蛋白酶（3Cpro）为靶点，设计并合成了一系列新的拟肽醛类化合物。大部分化合物都表现出很强的抗病毒活性，其中化合物18 p表现出较强的酶抑制活性和广谱抗肠道病毒和鼻病毒活性。在1.2 μ m的分辨率下测定的EV 71 3Cpro与18 p复合的晶体结构显示18 p与具有催化作用的Cys 147共价连接。此外，这些化合物对3CLpro和SARS冠状病毒2型（SARS-CoV-2）的复制也有较好的抑制活性，其中化合物18 p的抑制活性最强（IC 50 = 0.034 μM，EC 50 = 0.29 μM）。根据我们以前的工作，这些化合物没有理由担心急性毒性。与AG 7088相比，化合物18 p还表现出良好的药代动力学特性和更强的抗病毒活性，使其成为进一步开发的优秀先导。
A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3Cpro) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound 18p demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3Cpro in complex with 18p determined at a resolution of 1.2 Å revealed that 18p covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CLpro and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound 18p (IC50 = 0.034 μM, EC50 = 0.29 μM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with AG7088, compound 18p also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.