Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Alice Douangamath; Daren Fearon; Paul Gehrtz; Tobias Krojer; Petra Lukacik; C. David Owen; Efrat Resnick; Claire Strain-Damerell; Anthony Aimon; Péter Ábrányi-Balogh; José Brandão-Neto; Anna Carbery; Gemma Davison; Alexandre Dias; Thomas D. Downes; Louise Dunnett; Michael Fairhead; James D. Firth; S. Paul Jones; Aaron Keeley; György M. Keserü; Hanna F. Klein; Mathew P. Martin; Martin E.M. Noble; Peter O’Brien; Ailsa Powell; Rambabu N. Reddi; Rachael Skyner; Matthew Snee; Michael J. Waring; Conor Wild; Nir London; Frank von Delft; Martin A. Walsh

doi:10.1038/s41467-020-18709-w

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Alice Douangamath
, Daren Fearon
, Paul Gehrtz
, Tobias Krojer
, Petra Lukacik
, C. David Owen
, Efrat Resnick
, Claire Strain-Damerell
, Anthony Aimon
, Péter Ábrányi-Balogh
, José Brandão-Neto
, Anna Carbery
, Gemma Davison
, Alexandre Dias
, Thomas D. Downes
, Louise Dunnett
, Michael Fairhead
, James D. Firth
, S. Paul Jones
, Aaron Keeley

György M. Keserü, Hanna F. Klein, Mathew P. Martin, Martin E.M. Noble, Peter O’Brien, Ailsa Powell, Rambabu N. Reddi, Rachael Skyner, Matthew Snee, Michael J. Waring, Conor Wild, Nir London, Frank von Delft^*, Martin A. Walsh

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	5047
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18709-w
Publication status	Published - 7 Oct 2020

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10.1038/s41467-020-18709-w

s41467-020-18709-w
© 2020, The Author(s).
Final published version, 2.63 MBLicence: CC BY

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Douangamath, A., Fearon, D., Gehrtz, P., Krojer, T., Lukacik, P., Owen, C. D., Resnick, E., Strain-Damerell, C., Aimon, A., Ábrányi-Balogh, P., Brandão-Neto, J., Carbery, A., Davison, G., Dias, A., Downes, T. D., Dunnett, L., Fairhead, M., Firth, J. D., Jones, S. P., ... Walsh, M. A. (2020). Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease. Nature Communications, 11(1), Article 5047. https://doi.org/10.1038/s41467-020-18709-w

@article{59abb1d173ef49389e8841758db11c7b,

title = "Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease",

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.",

author = "Alice Douangamath and Daren Fearon and Paul Gehrtz and Tobias Krojer and Petra Lukacik and Owen, \{C. David\} and Efrat Resnick and Claire Strain-Damerell and Anthony Aimon and P{\'e}ter {\'A}br{\'a}nyi-Balogh and Jos{\'e} Brand{\~a}o-Neto and Anna Carbery and Gemma Davison and Alexandre Dias and Downes, \{Thomas D.\} and Louise Dunnett and Michael Fairhead and Firth, \{James D.\} and Jones, \{S. Paul\} and Aaron Keeley and Keser{\"u}, \{Gy{\"o}rgy M.\} and Klein, \{Hanna F.\} and Martin, \{Mathew P.\} and Noble, \{Martin E.M.\} and Peter O{\textquoteright}Brien and Ailsa Powell and Reddi, \{Rambabu N.\} and Rachael Skyner and Matthew Snee and Waring, \{Michael J.\} and Conor Wild and Nir London and \{von Delft\}, Frank and Walsh, \{Martin A.\}",

note = "{\textcopyright} 2020, The Author(s). ",

year = "2020",

month = oct,

day = "7",

doi = "10.1038/s41467-020-18709-w",

language = "English",

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journal = "Nature Communications",

issn = "2041-1723",

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Douangamath, A, Fearon, D, Gehrtz, P, Krojer, T, Lukacik, P, Owen, CD, Resnick, E, Strain-Damerell, C, Aimon, A, Ábrányi-Balogh, P, Brandão-Neto, J, Carbery, A, Davison, G, Dias, A, Downes, TD, Dunnett, L, Fairhead, M, Firth, JD, Jones, SP, Keeley, A, Keserü, GM, Klein, HF, Martin, MP, Noble, MEM, O’Brien, P, Powell, A, Reddi, RN, Skyner, R, Snee, M, Waring, MJ, Wild, C, London, N, von Delft, F & Walsh, MA 2020, 'Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease', Nature Communications, vol. 11, no. 1, 5047. https://doi.org/10.1038/s41467-020-18709-w

TY - JOUR

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AU - Douangamath, Alice

AU - Fearon, Daren

AU - Gehrtz, Paul

AU - Krojer, Tobias

AU - Lukacik, Petra

AU - Owen, C. David

AU - Resnick, Efrat

AU - Strain-Damerell, Claire

AU - Aimon, Anthony

AU - Ábrányi-Balogh, Péter

AU - Brandão-Neto, José

AU - Carbery, Anna

AU - Davison, Gemma

AU - Dias, Alexandre

AU - Downes, Thomas D.

AU - Dunnett, Louise

AU - Fairhead, Michael

AU - Firth, James D.

AU - Jones, S. Paul

AU - Keeley, Aaron

AU - Keserü, György M.

AU - Klein, Hanna F.

AU - Martin, Mathew P.

AU - Noble, Martin E.M.

AU - O’Brien, Peter

AU - Powell, Ailsa

AU - Reddi, Rambabu N.

AU - Skyner, Rachael

AU - Snee, Matthew

AU - Waring, Michael J.

AU - Wild, Conor

AU - London, Nir

AU - von Delft, Frank

AU - Walsh, Martin A.

PY - 2020/10/7

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N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85092204599

U2 - 10.1038/s41467-020-18709-w

DO - 10.1038/s41467-020-18709-w

M3 - Article

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AN - SCOPUS:85092204599

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5047

ER -

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

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Peter O'BRIEN

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Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

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Peter O'BRIEN

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