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PDBsum entry 2q6g
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References listed in PDB file
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Key reference
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Title
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Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design.
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Authors
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X.Xue,
H.Yu,
H.Yang,
F.Xue,
Z.Wu,
W.Shen,
J.Li,
Z.Zhou,
Y.Ding,
Q.Zhao,
X.C.Zhang,
M.Liao,
M.Bartlam,
Z.Rao.
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Ref.
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J Virol, 2008,
82,
2515-2527.
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PubMed id
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Abstract
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Coronaviruses (CoVs) can infect humans and multiple species of animals, causing
a wide spectrum of diseases. The coronavirus main protease (M(pro)), which plays
a pivotal role in viral gene expression and replication through the proteolytic
processing of replicase polyproteins, is an attractive target for anti-CoV drug
design. In this study, the crystal structures of infectious bronchitis virus
(IBV) M(pro) and a severe acute respiratory syndrome CoV (SARS-CoV) M(pro)
mutant (H41A), in complex with an N-terminal autocleavage substrate, were
individually determined to elucidate the structural flexibility and substrate
binding of M(pro). A monomeric form of IBV M(pro) was identified for the first
time in CoV M(pro) structures. A comparison of these two structures to other
available M(pro) structures provides new insights for the design of
substrate-based inhibitors targeting CoV M(pro)s. Furthermore, a Michael
acceptor inhibitor (named N3) was cocrystallized with IBV M(pro) and was found
to demonstrate in vitro inactivation of IBV M(pro) and potent antiviral activity
against IBV in chicken embryos. This provides a feasible animal model for
designing wide-spectrum inhibitors against CoV-associated diseases. The
structure-based optimization of N3 has yielded two more efficacious lead
compounds, N27 and H16, with potent inhibition against SARS-CoV M(pro).
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