Design of wide-spectrum inhibitors targeting coronavirus main proteases |
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| Authors: | Yang Haitao Xie Weiqing Xue Xiaoyu Yang Kailin Ma Jing Liang Wenxue Zhao Qi Zhou Zhe Pei Duanqing Ziebuhr John Hilgenfeld Rolf Yuen Kwok Yung Wong Luet Gao Guangxia Chen Saijuan Chen Zhu Ma Dawei Bartlam Mark Rao Zihe |
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| Affiliation: | 1 Tsinghua-IBP Joint Research Group for Structural Biology, Tsinghua University, Beijing, China, 2 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China, 3 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China, 4 Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Second Medical University, Shanghai, China, 5 Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China, 6 Institute of Virology and Immunology, University of Würzburg, Würzburg, Germany, 7 Institute for Biochemistry, University of Lübeck, Lübeck, Germany, 8 Department of Microbiology, University of Hong Kong, Hong Kong, China, 9 Department of Chemistry, Inorganic Chemistry Laboratory, University of Oxford, Oxford, United Kingdom |
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| Abstract: | The genus Coronavirus contains about 25 species of coronaviruses (CoVs), which are important pathogens causing highly prevalent diseases and often severe or fatal in humans and animals. No licensed specific drugs are available to prevent their infection. Different host receptors for cellular entry, poorly conserved structural proteins (antigens), and the high mutation and recombination rates of CoVs pose a significant problem in the development of wide-spectrum anti-CoV drugs and vaccines. CoV main proteases (Mpros), which are key enzymes in viral gene expression and replication, were revealed to share a highly conservative substrate-recognition pocket by comparison of four crystal structures and a homology model representing all three genetic clusters of the genus Coronavirus. This conclusion was further supported by enzyme activity assays. Mechanism-based irreversible inhibitors were designed, based on this conserved structural region, and a uniform inhibition mechanism was elucidated from the structures of Mpro-inhibitor complexes from severe acute respiratory syndrome-CoV and porcine transmissible gastroenteritis virus. A structure-assisted optimization program has yielded compounds with fast in vitro inactivation of multiple CoV Mpros, potent antiviral activity, and extremely low cellular toxicity in cell-based assays. Further modification could rapidly lead to the discovery of a single agent with clinical potential against existing and possible future emerging CoV-related diseases. |
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