Structure of the HRV-C 3C-Rupintrivir Complex Provides New Insights for Inhibitor Design
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RESEARCH ARTICLE
Structure of the HRV-C 3C-Rupintrivir Complex Provides New Insights for Inhibitor Design Shuai Yuan1,5 • Kaiyue Fan1,3 • Zhonghao Chen2,4 • Yao Sun1 • Hai Hou2,4
•
Ling Zhu1
Received: 21 August 2019 / Accepted: 25 December 2019 Ó Wuhan Institute of Virology, CAS 2020
Abstract 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. Keywords Human rhinoviruses (HRVs) 3C protease Three-dimensional structures Inhibitors Rupintrivir (AG7088)
Introduction
Kaiyue Fan and Zhonghao Chen have contributed equally to this work. & Hai Hou [email protected] & Ling Zhu [email protected] 1
CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
2
Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
3
Beijing Forestry University, No. 35 Tsinghua East Road, Haidian District, Beijing 100083, China
4
Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, China
5
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
Human rhinoviruses (HRVs), first discovered in the 1950s, are the predominant infectious agents of the common cold and the most common cause of upper respiratory tract infections worldwide (Arruda et al. 1997). In recent years, studies have shown that HRVs are responsible for the exacerbations of chronic pulmonary diseases and asthma (Johnston et al. 1995). Comprising about 160 serotypes, HRVs are divided into three groups HRV-A, HRV-B and HRV-C, utilizing intercellular adhesion molecule 1 (ICAM-1), low-density lipoprotein receptor (LDLR) and cadherin-related family member 3 (CDHR3) proteins, respectively, as receptors for host-cell entry (Greve et al. 1989; Hofer et al. 1
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