Synlett 2022; 33(05): 458-463
DOI: 10.1055/a-1582-0243
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Design and Chemical Synthesis of Antivirals

De novo Design of SARS-CoV-2 Main Protease Inhibitors

a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
,
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
b   Department of Chemistry, Ludwig-Maximilians-University Munich, Butenandtstrasse 5-13, 81377 München, Germany
,
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
,
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
,
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
,
Jessica N. Spradlin
c   Innovative Genomics Institute, University of California Berkeley, Berkeley, CA, 94720, USA
,
Dustin Dovala
d   Novartis Institutes for BioMedical Research, Emeryville, CA, 94608, USA
,
c   Innovative Genomics Institute, University of California Berkeley, Berkeley, CA, 94720, USA
,
Yingkai Zhang
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
,
Dirk Trauner
a   Department of Chemistry, New York University, 100 Washington Sq East, New York, NY, 10003, USA
› Author Affiliations
D.T. and his group are thankful for the COVID-19 Catalyst Grant by the New York University (NYU). Y.Z. would like to acknowledge the support by the National Institutes of Health (NIH, Grant No. R35 GM127040). C.F. thanks the Swiss National Science Foundation (SNSF, Grant No. 178569) for a postdoctoral fellowship. N.A.V. thanks the Studienstiftung des Deutschen Volkes (German Academic Scholarship Foundation) for a PhD Fellowship. Z.P. and K.P.R. are supported by the New York University (NYU) MacCracken Fellowship.


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Abstract

The COVID-19 pandemic prompted many scientists to investigate remedies against SARS-CoV-2 and related viruses that are likely to appear in the future. As the main protease of the virus, MPro, is highly conserved among coronaviruses, it has emerged as a prime target for developing inhibitors. Using a combination of virtual screening and molecular modeling, we identified small molecules that were easily accessible and could be quickly diversified. Biochemical assays confirmed a class of pyridones as low micromolar noncovalent inhibitors of the viral main protease.

Supporting Information



Publication History

Received: 13 July 2021

Accepted after revision: 10 August 2021

Accepted Manuscript online:
10 August 2021

Article published online:
05 October 2021

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