Design of wide-spectrum inhibitors targeting coronavirus main proteases.
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.
Yang
Haitao
H
Tsinghua-IBP Joint Research Group for Structural Biology, Tsinghua University, Beijing, China.
Xie
Weiqing
W
Xue
Xiaoyu
X
Yang
Kailin
K
Ma
Jing
J
Liang
Wenxue
W
Zhao
Qi
Q
Zhou
Zhe
Z
Pei
Duanqing
D
Ziebuhr
John
J
Hilgenfeld
Rolf
R
Yuen
Kwok Yung
KY
Wong
Luet
L
Gao
Guangxia
G
Chen
Saijuan
S
Chen
Zhu
Z
Ma
Dawei
D
Bartlam
Mark
M
Rao
Zihe
Z
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
D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D010080:Oxazoles; D011760:Pyrrolidinones; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases