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Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies

Altincekic, Nadide ; Jores, Nathalie ; Löhr, Frank ; Richter, Chrisitan ; Ehrhardt, Claus ; Blommers, Marcel J.J. ; Berg, Hannes ; Öztürk, Sare ; Gande, Santosh L. and Linhard, Verena , et al. (2024) In ACS Chemical Biology
Abstract

The main protease Mpro, nsp5, of SARS-CoV-2 (SCoV2) is one of its most attractive drug targets. Here, we report primary screening data using nuclear magnetic resonance spectroscopy (NMR) of four different libraries and detailed follow-up synthesis on the promising uracil-containing fragment Z604 derived from these libraries. Z604 shows time-dependent binding. Its inhibitory effect is sensitive to reducing conditions. Starting with Z604, we synthesized and characterized 13 compounds designed by fragment growth strategies. Each compound was characterized by NMR and/or activity assays to investigate their interaction with Mpro. 

These investigations resulted in the four-armed compound 35b that binds directly to... (More)

The main protease Mpro, nsp5, of SARS-CoV-2 (SCoV2) is one of its most attractive drug targets. Here, we report primary screening data using nuclear magnetic resonance spectroscopy (NMR) of four different libraries and detailed follow-up synthesis on the promising uracil-containing fragment Z604 derived from these libraries. Z604 shows time-dependent binding. Its inhibitory effect is sensitive to reducing conditions. Starting with Z604, we synthesized and characterized 13 compounds designed by fragment growth strategies. Each compound was characterized by NMR and/or activity assays to investigate their interaction with Mpro. 

These investigations resulted in the four-armed compound 35b that binds directly to Mpro. 35b could be cocrystallized with Mpro revealing its noncovalent binding mode, which fills all four active site subpockets. Herein, we describe the NMR-derived fragment-to-hit pipeline and its application for the development of promising starting points for inhibitors of the main protease of SCoV2.

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publishing date
type
Contribution to journal
publication status
epub
in
ACS Chemical Biology
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:38232960
  • scopus:85183508732
ISSN
1554-8929
DOI
10.1021/acschembio.3c00720
language
English
LU publication?
no
id
d417f796-617f-447c-b091-35eee265bbe2
date added to LUP
2024-02-08 13:40:30
date last changed
2024-04-24 20:15:33
@article{d417f796-617f-447c-b091-35eee265bbe2,
  abstract     = {{<p>The main protease M<sup>pro</sup>, nsp5, of SARS-CoV-2 (SCoV2) is one of its most attractive drug targets. Here, we report primary screening data using nuclear magnetic resonance spectroscopy (NMR) of four different libraries and detailed follow-up synthesis on the promising uracil-containing fragment Z604 derived from these libraries. Z604 shows time-dependent binding. Its inhibitory effect is sensitive to reducing conditions. Starting with Z604, we synthesized and characterized 13 compounds designed by fragment growth strategies. Each compound was characterized by NMR and/or activity assays to investigate their interaction with M<sup>pro</sup>. </p><p>These investigations resulted in the four-armed compound 35b that binds directly to M<sup>pro</sup>. 35b could be cocrystallized with M<sup>pro</sup> revealing its noncovalent binding mode, which fills all four active site subpockets. Herein, we describe the NMR-derived fragment-to-hit pipeline and its application for the development of promising starting points for inhibitors of the main protease of SCoV2.</p>}},
  author       = {{Altincekic, Nadide and Jores, Nathalie and Löhr, Frank and Richter, Chrisitan and Ehrhardt, Claus and Blommers, Marcel J.J. and Berg, Hannes and Öztürk, Sare and Gande, Santosh L. and Linhard, Verena and Orts, Julien and Abdi Saad, Marie Jose and Bütikofer, Matthias and Kaderli, Janina and Karlsson, B. Göran and Brath, Ulrika and Hedenström, Mattias and Gröbner, Gerhard and Sauer, Uwe H. and Perrakis, Anastassis and Langer, Julian and Banci, Lucia and Cantini, Francesca and Fragai, Marco and Grifagni, Deborah and Barthel, Tatjana and Wollenhaupt, Jan and Weiss, Manfred S. and Robertson, Angus and Bax, Adriaan and Sreeramulu, Sridhar and Schwalbe, Harald}},
  issn         = {{1554-8929}},
  language     = {{eng}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Chemical Biology}},
  title        = {{Targeting the Main Protease (M<sup>pro</sup>, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies}},
  url          = {{http://dx.doi.org/10.1021/acschembio.3c00720}},
  doi          = {{10.1021/acschembio.3c00720}},
  year         = {{2024}},
}