Structures of Two Coronavirus Main Proteases: Implications for Substrate Binding and Antiviral Drug Design

Author:

Xue Xiaoyu12,Yu Hongwei3,Yang Haitao12,Xue Fei12,Wu Zhixin3,Shen Wei12,Li Jun12,Zhou Zhe1,Ding Yi1,Zhao Qi12,Zhang Xuejun C.2,Liao Ming3,Bartlam Mark124,Rao Zihe124

Affiliation:

1. Tsinghua-Nankai-IBP Joint Research Group for Structural Biology, Tsinghua University, Beijing 100084, China

2. National Laboratory of Biomacromolecules, Institute of Biophysics (IBP), Chinese Academy of Sciences, Beijing 100101, China

3. Laboratory of Avian Medicine, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China

4. College of Life Sciences, Nankai University, Tianjin 300071, China

Abstract

ABSTRACT Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M pro ), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) M pro and a severe acute respiratory syndrome CoV (SARS-CoV) M pro mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M pro . A monomeric form of IBV M pro was identified for the first time in CoV M pro structures. A comparison of these two structures to other available M pro structures provides new insights for the design of substrate-based inhibitors targeting CoV M pro s. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M pro and was found to demonstrate in vitro inactivation of IBV M pro and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M pro .

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3