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Identification of fragments binding to SARS-CoV-2 nsp10 reveals ligand-binding sites in conserved interfaces between nsp10 and nsp14/nsp16

Kozielski, Frank LU ; Sele, Céleste LU ; Talibov, Vladimir O. LU orcid ; Lou, Jiaqi ; Dong, Danni ; Wang, Qian ; Shi, Xinyue ; Nyblom, Maria LU ; Rogstam, Annika LU and Krojer, Tobias LU orcid , et al. (2021) In RSC Chemical Biology 3(1). p.44-55
Abstract
Since the emergence of SARS-CoV-2 in 2019, Covid-19 has developed into a serious threat to our health, social and economic systems. Although vaccines have been developed in a tour-de-force and are now increasingly available, repurposing of existing drugs has been less successful. There is a clear need to develop new drugs against SARS-CoV-2 that can also be used against future coronavirus infections. Non-structural protein 10 (nsp10) is a conserved stimulator of two enzymes crucial for viral replication, nsp14 and nsp16, exhibiting exoribonuclease and methyltransferase activities. Interfering with RNA proofreading or RNA cap formation represents intervention strategies to inhibit replication. We applied fragment-based screening using nano... (More)
Since the emergence of SARS-CoV-2 in 2019, Covid-19 has developed into a serious threat to our health, social and economic systems. Although vaccines have been developed in a tour-de-force and are now increasingly available, repurposing of existing drugs has been less successful. There is a clear need to develop new drugs against SARS-CoV-2 that can also be used against future coronavirus infections. Non-structural protein 10 (nsp10) is a conserved stimulator of two enzymes crucial for viral replication, nsp14 and nsp16, exhibiting exoribonuclease and methyltransferase activities. Interfering with RNA proofreading or RNA cap formation represents intervention strategies to inhibit replication. We applied fragment-based screening using nano differential scanning fluorometry and X-ray crystallography to identify ligands targeting SARS-CoV-2 nsp10. We identified four fragments located in two distinct sites: one can be modelled to where it would be located in the nsp14–nsp10 complex interface and the other in the nsp16–nsp10 complex interface. Microscale thermophoresis (MST) experiments were used to quantify fragment affinities for nsp10. Additionally, we showed by MST that the interaction by nsp14 and 10 is weak and thereby that complex formation could be disrupted by small molecules. The fragments will serve as starting points for the development of more potent analogues using fragment growing techniques and structure-based drug design. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
RSC Chemical Biology
volume
3
issue
1
pages
12 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:85122866011
ISSN
2633-0679
DOI
10.1039/D1CB00135C
language
English
LU publication?
yes
id
218c17de-7b0a-4bd5-8f80-74af8175970c
date added to LUP
2021-10-24 16:20:01
date last changed
2022-08-02 13:15:07
@article{218c17de-7b0a-4bd5-8f80-74af8175970c,
  abstract     = {{Since the emergence of SARS-CoV-2 in 2019, Covid-19 has developed into a serious threat to our health, social and economic systems. Although vaccines have been developed in a tour-de-force and are now increasingly available, repurposing of existing drugs has been less successful. There is a clear need to develop new drugs against SARS-CoV-2 that can also be used against future coronavirus infections. Non-structural protein 10 (nsp10) is a conserved stimulator of two enzymes crucial for viral replication, nsp14 and nsp16, exhibiting exoribonuclease and methyltransferase activities. Interfering with RNA proofreading or RNA cap formation represents intervention strategies to inhibit replication. We applied fragment-based screening using nano differential scanning fluorometry and X-ray crystallography to identify ligands targeting SARS-CoV-2 nsp10. We identified four fragments located in two distinct sites: one can be modelled to where it would be located in the nsp14–nsp10 complex interface and the other in the nsp16–nsp10 complex interface. Microscale thermophoresis (MST) experiments were used to quantify fragment affinities for nsp10. Additionally, we showed by MST that the interaction by nsp14 and 10 is weak and thereby that complex formation could be disrupted by small molecules. The fragments will serve as starting points for the development of more potent analogues using fragment growing techniques and structure-based drug design.}},
  author       = {{Kozielski, Frank and Sele, Céleste and Talibov, Vladimir O. and Lou, Jiaqi and Dong, Danni and Wang, Qian and Shi, Xinyue and Nyblom, Maria and Rogstam, Annika and Krojer, Tobias and Fisher, Zoë and Knecht, Wolfgang}},
  issn         = {{2633-0679}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{1}},
  pages        = {{44--55}},
  publisher    = {{Royal Society of Chemistry}},
  series       = {{RSC Chemical Biology}},
  title        = {{Identification of fragments binding to SARS-CoV-2 nsp10 reveals ligand-binding sites in conserved interfaces between nsp10 and nsp14/nsp16}},
  url          = {{http://dx.doi.org/10.1039/D1CB00135C}},
  doi          = {{10.1039/D1CB00135C}},
  volume       = {{3}},
  year         = {{2021}},
}