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PDBsum entry 7lcp
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Viral protein,hydrolase/inhibitor
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PDB id
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7lcp
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References listed in PDB file
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Key reference
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Title
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N-Terminal finger stabilizes the s1 pocket for the reversible feline drug gc376 in the sars-Cov-2 mpro dimer.
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Authors
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E.Arutyunova,
M.B.Khan,
C.Fischer,
J.Lu,
T.Lamer,
W.Vuong,
M.J.Van belkum,
R.T.Mckay,
D.L.Tyrrell,
J.C.Vederas,
H.S.Young,
M.J.Lemieux.
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Ref.
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J Mol Biol, 2021,
433,
167003.
[DOI no: ]
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PubMed id
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Abstract
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The main protease (Mpro, also known as 3CL protease) of SARS-CoV-2 is
a high priority drug target in the development of antivirals to combat COVID-19
infections. A feline coronavirus antiviral drug, GC376, has been shown to be
effective in inhibiting the SARS-CoV-2 main protease and live virus growth. As
this drug moves into clinical trials, further characterization of GC376 with the
main protease of coronaviruses is required to gain insight into the drug's
properties, such as reversibility and broad specificity. Reversibility is an
important factor for therapeutic proteolytic inhibitors to prevent toxicity due
to off-target effects. Here we demonstrate that GC376 has nanomolar
Ki values with the Mpro from both SARS-CoV-2 and SARS-CoV
strains. Restoring enzymatic activity after inhibition by GC376 demonstrates
reversible binding with both proteases. In addition, the stability and
thermodynamic parameters of both proteases were studied to shed light on
physical chemical properties of these viral enzymes, revealing higher stability
for SARS-CoV-2 Mpro. The comparison of a new X-ray crystal structure
of Mpro from SARS-CoV complexed with GC376 reveals similar molecular
mechanism of inhibition compared to SARS-CoV-2 Mpro, and gives
insight into the broad specificity properties of this drug. In both structures,
we observe domain swapping of the N-termini in the dimer of the Mpro,
which facilitates coordination of the drug's P1 position. These results validate
that GC376 is a drug with an off-rate suitable for clinical trials.
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