title: Design of wide-spectrum inhibitors targeting coronavirus main proteases.
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 (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.
authors.affiliation: Tsinghua-IBP Joint Research Group for Structural Biology, Tsinghua University, Beijing, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Yang
authors.forename: Weiqing
authors.initials: W
authors.lastname: Xie
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xue
authors.forename: Kailin
authors.initials: K
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Wenxue
authors.initials: W
authors.lastname: Liang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
authors.forename: John
authors.initials: J
authors.lastname: Ziebuhr
authors.forename: Rolf
authors.initials: R
authors.lastname: Hilgenfeld
authors.forename: Kwok Yung
authors.initials: KY
authors.lastname: Yuen
authors.forename: Luet
authors.initials: L
authors.lastname: Wong
authors.forename: Guangxia
authors.initials: G
authors.lastname: Gao
authors.forename: Saijuan
authors.initials: S
authors.lastname: Chen
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Dawei
authors.initials: D
authors.lastname: Ma
authors.forename: Mark
authors.initials: M
authors.lastname: Bartlam
authors.forename: Zihe
authors.initials: Z
authors.lastname: Rao
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D017934:Coronavirus / Q000201:enzymology*; D000086782:Coronavirus 3C Proteases; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis / Q000494:pharmacology; D011487:Protein Conformation; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology; D005760:Transmissible gastroenteritis virus / Q000201:enzymology; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000037:antagonists & inhibitors
chemical_list: D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D010080:Oxazoles; D011760:Pyrrolidinones; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases