Статья

Design of Wide-Spectrum Inhibitors Targeting Coronavirus Main Proteases

Haitao YangTsinghua-IBP Joint Research Group for Structural Biology, Tsinghua University, Beijing, ChinaWeiqing XieState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaXiaoyu XueNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaKailin YangNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaJing MaNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaWenxue LiangShanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Second Medical University, Shanghai, ChinaQi ZhaoNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaZhe ZhouNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaDuanqing PeiGuangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, ChinaJohn ZiebuhrInstitute of Virology and Immunology, University of Würzburg, Würzburg, GermanyR. HilgenfeldInstitute for Biochemistry, University of Lübeck, Lübeck, GermanyKwok‐Yung YuenDepartment of Microbiology, University of Hong Kong, Hong Kong, ChinaLuet‐Lok WongDepartment of Chemistry, Inorganic Chemistry Laboratory, University of Oxford, Oxford, United KingdomGuangxia GaoNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaSai‐Juan ChenShanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Second Medical University, Shanghai, ChinaChen ZhuShanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Second Medical University, Shanghai, ChinaDawei MaState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaMark BartlamNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaZihe RaoNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

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Аннотация

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 (M(pro)s), 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 M(pro)s, 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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Идентификаторы

DOI: 10.1371/journal.pbio.0030324

Цитирования и источники

Цитирований: 3Использованных источников: 0

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