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PDBsum entry 1wof
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References listed in PDB file
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Key reference
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Title
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Design of wide-Spectrum inhibitors targeting coronavirus main proteases.
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Authors
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H.Yang,
W.Xie,
X.Xue,
K.Yang,
J.Ma,
W.Liang,
Q.Zhao,
Z.Zhou,
D.Pei,
J.Ziebuhr,
R.Hilgenfeld,
K.Y.Yuen,
L.Wong,
G.Gao,
S.Chen,
Z.Chen,
D.Ma,
M.Bartlam,
Z.Rao.
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Ref.
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Plos Biol, 2005,
3,
e324-334.
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PubMed id
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Abstract
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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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