Yuan Shuai, Fan Kaiyue, Chen Zhonghao, Sun Yao, Hou Hai, Zhu Ling
CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06511, USA.
Virol Sin. 2020 Aug;35(4):445-454. doi: 10.1007/s12250-020-00196-4. Epub 2020 Feb 26.
Human rhinoviruses (HRVs) are the predominant infectious agents for the common cold worldwide. The HRV-C species cause severe illnesses in children and are closely related to acute exacerbations of asthma. 3C protease, a highly conserved enzyme, cleaves the viral polyprotein during replication and assists the virus in escaping the host immune system. These key roles make 3C protease an important drug target. A few structures of 3Cs complexed with an irreversible inhibitor rupintrivir have been determined. These structures shed light on the determinants of drug specificity. Here we describe the structures of HRV-C15 3C in free and inhibitor-bound forms. The volume-decreased S1' subsite and half-closed S2 subsite, which were thought to be unique features of enterovirus A 3C proteases, appear in the HRV-C 3C protease. Rupintrivir assumes an "intermediate" conformation in the complex, which might open up additional avenues for the design of potent antiviral inhibitors. Analysis of the features of the three-dimensional structures and the amino acid sequences of 3C proteases suggest new applications for existing drugs.
人鼻病毒（HRVs）是全球普通感冒的主要感染源。HRV-C 型病毒可导致儿童患上严重疾病，且与哮喘急性加重密切相关。3C 蛋白酶是一种高度保守的酶，在病毒复制过程中切割病毒多聚蛋白，并帮助病毒逃避免疫系统。这些关键作用使 3C 蛋白酶成为一个重要的药物靶点。已确定了一些 3C 与不可逆抑制剂卢匹那韦形成的复合物的结构。这些结构揭示了药物特异性的决定因素。在此，我们描述了 HRV-C15 3C 处于游离态和与抑制剂结合态的结构。体积减小的 S1' 亚位点和半封闭的 S2 亚位点，被认为是肠道病毒 A 型 3C 蛋白酶的独特特征，在 HRV-C 3C 蛋白酶中也有出现。卢匹那韦在复合物中呈现出“中间”构象，这可能为设计强效抗病毒抑制剂开辟新途径。对 3C 蛋白酶三维结构和氨基酸序列特征的分析为现有药物提出了新的应用方向。
