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

Nadide Altincekic; Nathalie Jores; Frank Löhr; Christian Richter; Claus Ehrhardt; Marcel J J Blommers; Hannes Berg; Sare Öztürk; Santosh L Gande; Verena Linhard; Julien Orts; Marie Jose Abi Saad; Matthias Bütikofer; Janina Kaderli; B Göran Karlsson; Ulrika Brath; Mattias Hedenström; Uwe H Sauer; Anastassis Perrakis; Julian Langer; Lucia Banci; Francesca Cantini; Marco Fragai; Deborah Grifagni; Tatjana Barthel; Jan Wollenhaupt; Angus Robertson; Adriaan Bax; Sridhar Sreeramulu; Harald Schwalbe

doi:10.1021/acschembio.3c00720

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

Nadide Altincekic (Corresponding author), Nathalie Jores, Frank Löhr, Christian Richter, Claus Ehrhardt, Marcel J J Blommers, Hannes Berg, Sare Öztürk, Santosh L Gande, Verena Linhard, Julien Orts, Marie Jose Abi Saad, Matthias Bütikofer, Janina Kaderli, B Göran Karlsson, Ulrika Brath, Mattias Hedenström, Uwe H Sauer, Anastassis Perrakis, Julian LangerLucia Banci, Francesca Cantini, Marco Fragai, Deborah Grifagni, Tatjana Barthel, Jan Wollenhaupt, Angus Robertson, Adriaan Bax, Sridhar Sreeramulu, Harald Schwalbe (Corresponding author)

Department of Pharmaceutical Sciences

Publications: Contribution to journal › Article › Peer Reviewed

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 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.

Original language	English
Pages (from-to)	563-574
Number of pages	12
Journal	ACS Chemical Biology
Volume	19
Issue number	2
Early online date	17 Jan 2024
DOIs	https://doi.org/10.1021/acschembio.3c00720
Publication status	Published - 16 Feb 2024

Austrian Fields of Science 2012

106006 Biophysics
104026 Spectroscopy
301207 Pharmaceutical chemistry

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10.1021/acschembio.3c00720

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Altincekic, N., Jores, N., Löhr, F., Richter, C., Ehrhardt, C., Blommers, M. J. J., Berg, H., Öztürk, S., Gande, S. L., Linhard, V., Orts, J., Abi Saad, M. J., Bütikofer, M., Kaderli, J., Karlsson, B. G., Brath, U., Hedenström, M., Sauer, U. H., Perrakis, A., ... Schwalbe, H. (2024). Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies. ACS Chemical Biology, 19(2), 563-574. https://doi.org/10.1021/acschembio.3c00720

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

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 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.",

author = "Nadide Altincekic and Nathalie Jores and Frank L{\"o}hr and Christian Richter and Claus Ehrhardt and Blommers, {Marcel J J} and Hannes Berg and Sare {\"O}zt{\"u}rk and Gande, {Santosh L} and Verena Linhard and Julien Orts and {Abi Saad}, {Marie Jose} and Matthias B{\"u}tikofer and Janina Kaderli and Karlsson, {B G{\"o}ran} and Ulrika Brath and Mattias Hedenstr{\"o}m and Sauer, {Uwe H} and Anastassis Perrakis and Julian Langer and Lucia Banci and Francesca Cantini and Marco Fragai and Deborah Grifagni and Tatjana Barthel and Jan Wollenhaupt and Angus Robertson and Adriaan Bax and Sridhar Sreeramulu and Harald Schwalbe",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Published by American Chemical Society.",

year = "2024",

month = feb,

day = "16",

doi = "10.1021/acschembio.3c00720",

language = "English",

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Altincekic, N, Jores, N, Löhr, F, Richter, C, Ehrhardt, C, Blommers, MJJ, Berg, H, Öztürk, S, Gande, SL, Linhard, V, Orts, J , Abi Saad, MJ, Bütikofer, M, Kaderli, J, Karlsson, BG, Brath, U, Hedenström, M, Sauer, UH, Perrakis, A, Langer, J, Banci, L, Cantini, F, Fragai, M, Grifagni, D, Barthel, T, Wollenhaupt, J, Robertson, A, Bax, A, Sreeramulu, S & Schwalbe, H 2024, 'Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies', ACS Chemical Biology, vol. 19, no. 2, pp. 563-574. https://doi.org/10.1021/acschembio.3c00720

TY - JOUR

T1 - Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies

AU - Altincekic, Nadide

AU - Jores, Nathalie

AU - Löhr, Frank

AU - Richter, Christian

AU - Ehrhardt, Claus

AU - Blommers, Marcel J J

AU - Berg, Hannes

AU - Öztürk, Sare

AU - Gande, Santosh L

AU - Linhard, Verena

AU - Orts, Julien

AU - Abi Saad, Marie Jose

AU - Bütikofer, Matthias

AU - Kaderli, Janina

AU - Karlsson, B Göran

AU - Brath, Ulrika

AU - Hedenström, Mattias

AU - Sauer, Uwe H

AU - Perrakis, Anastassis

AU - Langer, Julian

AU - Banci, Lucia

AU - Cantini, Francesca

AU - Fragai, Marco

AU - Grifagni, Deborah

AU - Barthel, Tatjana

AU - Wollenhaupt, Jan

AU - Robertson, Angus

AU - Bax, Adriaan

AU - Sreeramulu, Sridhar

AU - Schwalbe, Harald

PY - 2024/2/16

Y1 - 2024/2/16

N2 - 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.

AB - 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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DO - 10.1021/acschembio.3c00720

M3 - Article

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VL - 19

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EP - 574

JO - ACS Chemical Biology

JF - ACS Chemical Biology

SN - 1554-8929

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ER -

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

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Austrian Fields of Science 2012

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