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Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
DOI:
10.1038/s41467-020-18709-w
Authors:
Alice
Douangamath
(Diamond Light Source; Research Complex at Harwell)
,
Daren
Fearon
(Diamond Light Source)
,
Paul
Gehrtz
(Weizmann Institute of Science)
,
Tobias
Krojer
(Structural Genomics Consortium, University of Oxford)
,
Petra
Lukacik
(Diamond Light Source; Research Complex at Harwell)
,
C. David
Owen
(Diamond Light Source; Research Complex at Harwell)
,
Efrat
Resnick
(Weizmann Institute of Science)
,
Claire
Strain-Damerell
(Diamond Light Source; Research Complex at Harwell)
,
Anthony
Aimon
(Diamond Light Source; Research Complex at Harwell)
,
Péter
Ábrányi-Balogh
(Research Centre for Natural Sciences (RCNS-HAS))
,
Jose
Brandao-Neto
(Diamond Light Source; Research Complex at Harwell)
,
Anna
Carbery
(Diamond Light Source; University of Oxford)
,
Gemma
Davison
(Newcastle University)
,
Alexandre
Dias
(Diamond Light Source)
,
Thomas D.
Downes
(University of York)
,
Louise
Dunnett
(Diamond Light Source)
,
Michael
Fairhead
(Structural Genomics Consortium, University of Oxford)
,
James D.
Firth
(University of York)
,
S. Paul
Jones
(University of York)
,
Aaron
Keeley
(Research Centre for Natural Sciences (RCNS-HAS))
,
György M.
Keserü
(Research Centre for Natural Sciences (RCNS-HAS))
,
Hanna F.
Klein
(University of York)
,
Mathew P.
Martin
(Newcastle University)
,
Martin M.
Noble
(Newcastle University)
,
Peter
O’brien
(University of York)
,
Ailsa
Powell
(Diamond Light Source)
,
Rambabu N.
Reddi
(Weizmann Institute of Science)
,
Rachael
Skyner
(Diamond Light Source; Research Complex at Harwell)
,
Matthew
Snee
(Diamond Light Source)
,
Michael J.
Waring
(Newcastle University)
,
Conor
Wild
(Diamond Light Source)
,
Nir
London
(Weizmann Institute of Science)
,
Frank
Von Delft
(Diamond Light Source)
,
Martin A.
Walsh
(Diamond Light Source)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Nature Communications
, VOL 11
State:
Published (Approved)
Published:
October 2020

Abstract: COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.
Journal Keywords: Enzymes; Mass spectrometry; Proteases; X-ray crystallography
Diamond Keywords: COVID-19; Viruses
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Diamond Offline Facilities:
XChem
Instruments:
I04-1-Macromolecular Crystallography (fixed wavelength)
,
I04-Macromolecular Crystallography
Added On:
09/10/2020 13:15
Documents:
s41467-020-18709-w.pdf
Discipline Tags:
Pathogens
Infectious Diseases
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)
Fragment Screening