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Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development

Berg, Hannes ; Schwalbe, Harald and Robertson, Angus LU (2022) In Angewandte Chemie - International Edition 61(46).
Abstract
SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these... (More)
SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome. © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. (Less)
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author
; and
author collaboration
publishing date
type
Contribution to journal
publication status
published
keywords
COVID19-NMR, Drug Discovery, Fragment Screening, NMR Spectroscopy, Protein, SARS-CoV-2
in
Angewandte Chemie - International Edition
volume
61
issue
46
article number
e202205858
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85139756352
ISSN
1521-3773
DOI
10.1002/anie.202205858
language
English
LU publication?
no
id
4237954a-2ea6-4017-a78f-d98a5b168628
date added to LUP
2024-01-30 09:13:21
date last changed
2024-01-30 09:15:22
@article{4237954a-2ea6-4017-a78f-d98a5b168628,
  abstract     = {{SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome. © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.}},
  author       = {{Berg, Hannes and Schwalbe, Harald and Robertson, Angus}},
  issn         = {{1521-3773}},
  keywords     = {{COVID19-NMR; Drug Discovery; Fragment Screening; NMR Spectroscopy; Protein; SARS-CoV-2}},
  language     = {{eng}},
  number       = {{46}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Angewandte Chemie - International Edition}},
  title        = {{Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development}},
  url          = {{http://dx.doi.org/10.1002/anie.202205858}},
  doi          = {{10.1002/anie.202205858}},
  volume       = {{61}},
  year         = {{2022}},
}