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

Hannes Berg; Maria A. Wirtz Martin; Nadide Altincekic; Islam Alshamleh; Jasleen Kaur Bains; Julius Blechar; Betul Ceylan; Vanessa de Jesus; Karthikeyan Dhamotharan; Christin Fuks; Santosh L. Gande; Bruno Hargittay; Katharina F. Hohmann; Marie T. Hutchison; Sophie Marianne Korn; Robin Krishnathas; Felicitas Kutz; Verena Linhard; Tobias Matzel; Nathalie Meiser; Anna Niesteruk; Dennis J. Pyper; Linda Schulte; Sven Trucks; Kamal Azzaoui; Marcel J. J. Blommers; Yojana Gadiya; Reagon Karki; Andrea Zaliani; Philip Gribbon; Marcius da Silva Almeida; Cristiane Dinis Anobom; Anna L. Bula; Matthias Butikofer; Icaro Putinhon Caruso; Isabella Caterina Felli; Andrea T. Da Poian; Gisele Cardoso de Amorim; Nikolaos K. Fourkiotis; Angelo Gallo; Dhiman Ghosh; Francisco Gomes-Neto; Oksana Gorbatyuk; Bing Hao; Vilius Kurauskas; Lauriane Lecoq; Yunfeng Li; Nathane Cunha Mebus-Antunes; Miguel Mompean; Thais Cristtina Neves-Martins; Marti Ninot-Pedrosa; Anderson S. Pinheiro; Letizia Pontoriero; Yulia Pustovalova; Roland Riek; Angus J. Robertson; Marie Jose Abi Saad; Miguel A. Trevino; Aikaterini C. Tsika; Fabio C. L. Almeida; Ad Bax; Katherine Henzler-Wildman; Jeffrey C. Hoch; Kristaps Jaudzems; Douglas Laurents; Julien Orts; Roberta Pierattelli; Georgios A. Spyroulias; Elke Duchardt-Ferner; Jan Ferner; Boris Fürtig; Martin Hengesbach; Frank Lohr; Nusrat Qureshi; Christian Richter; Krishna Saxena; Andreas Schlundt; Sridhar Sreeramulu; Anna Wacker; Julia E. Weigand; Julia Wirmer-Bartoschek; Jens Wohnert; Harald Schwalbe

doi:10.1002/anie.202205858

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

Hannes Berg, Maria A. Wirtz Martin, Nadide Altincekic, Islam Alshamleh, Jasleen Kaur Bains, Julius Blechar, Betul Ceylan, Vanessa de Jesus, Karthikeyan Dhamotharan, Christin Fuks, Santosh L. Gande, Bruno Hargittay, Katharina F. Hohmann, Marie T. Hutchison, Sophie Marianne Korn, Robin Krishnathas, Felicitas Kutz, Verena Linhard, Tobias Matzel, Nathalie MeiserAnna Niesteruk, Dennis J. Pyper, Linda Schulte, Sven Trucks, Kamal Azzaoui, Marcel J. J. Blommers, Yojana Gadiya, Reagon Karki, Andrea Zaliani, Philip Gribbon, Marcius da Silva Almeida, Cristiane Dinis Anobom, Anna L. Bula, Matthias Butikofer, Icaro Putinhon Caruso, Isabella Caterina Felli, Andrea T. Da Poian, Gisele Cardoso de Amorim, Nikolaos K. Fourkiotis, Angelo Gallo, Dhiman Ghosh, Francisco Gomes-Neto, Oksana Gorbatyuk, Bing Hao, Vilius Kurauskas, Lauriane Lecoq, Yunfeng Li, Nathane Cunha Mebus-Antunes, Miguel Mompean, Thais Cristtina Neves-Martins, Marti Ninot-Pedrosa, Anderson S. Pinheiro, Letizia Pontoriero, Yulia Pustovalova, Roland Riek, Angus J. Robertson, Marie Jose Abi Saad, Miguel A. Trevino, Aikaterini C. Tsika, Fabio C. L. Almeida, Ad Bax, Katherine Henzler-Wildman, Jeffrey C. Hoch, Kristaps Jaudzems, Douglas Laurents, Julien Orts, Roberta Pierattelli, Georgios A. Spyroulias, Elke Duchardt-Ferner, Jan Ferner, Boris Fürtig, Martin Hengesbach, Frank Lohr, Nusrat Qureshi, Christian Richter, Krishna Saxena, Andreas Schlundt, Sridhar Sreeramulu, Anna Wacker, Julia E. Weigand, Julia Wirmer-Bartoschek, Jens Wohnert, Harald Schwalbe

Department of Pharmaceutical Sciences

Publications: Contribution to journal › Article › Peer Reviewed

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.

Original language	English
Article number	e202205858
Number of pages	12
Journal	Angewandte Chemie International Edition
Volume	61
Issue number	46
DOIs	https://doi.org/10.1002/anie.202205858
Publication status	Published - 14 Nov 2022

Austrian Fields of Science 2012

106002 Biochemistry
106006 Biophysics

Keywords

COVID19-NMR
Drug Discovery
Fragment Screening
NMR Spectroscopy
Protein
SARS-CoV-2
SMALL-MOLECULE INHIBITORS
ANTIVIRAL COMPOUNDS
CORONAVIRUS
DISCOVERY
FEATURES
OMICRON

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/anie.202205858Licence: CC BY 4.0

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Berg, H., Martin, M. A. W., Altincekic, N., Alshamleh, I., Bains, J. K., Blechar, J., Ceylan, B., de Jesus, V., Dhamotharan, K., Fuks, C., Gande, S. L., Hargittay, B., Hohmann, K. F., Hutchison, M. T., Korn, S. M., Krishnathas, R., Kutz, F., Linhard, V., Matzel, T., ... Schwalbe, H. (2022). Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development. Angewandte Chemie International Edition, 61(46), [e202205858]. https://doi.org/10.1002/anie.202205858

@article{f60e22445b3944ca84975ca228028839,

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

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.",

keywords = "COVID19-NMR, Drug Discovery, Fragment Screening, NMR Spectroscopy, Protein, SARS-CoV-2, SMALL-MOLECULE INHIBITORS, ANTIVIRAL COMPOUNDS, CORONAVIRUS, DISCOVERY, FEATURES, OMICRON",

author = "Hannes Berg and Martin, {Maria A. Wirtz} and Nadide Altincekic and Islam Alshamleh and Bains, {Jasleen Kaur} and Julius Blechar and Betul Ceylan and {de Jesus}, Vanessa and Karthikeyan Dhamotharan and Christin Fuks and Gande, {Santosh L.} and Bruno Hargittay and Hohmann, {Katharina F.} and Hutchison, {Marie T.} and Korn, {Sophie Marianne} and Robin Krishnathas and Felicitas Kutz and Verena Linhard and Tobias Matzel and Nathalie Meiser and Anna Niesteruk and Pyper, {Dennis J.} and Linda Schulte and Sven Trucks and Kamal Azzaoui and Blommers, {Marcel J. J.} and Yojana Gadiya and Reagon Karki and Andrea Zaliani and Philip Gribbon and Almeida, {Marcius da Silva} and Anobom, {Cristiane Dinis} and Bula, {Anna L.} and Matthias Butikofer and Caruso, {Icaro Putinhon} and Felli, {Isabella Caterina} and {Da Poian}, {Andrea T.} and {de Amorim}, {Gisele Cardoso} and Fourkiotis, {Nikolaos K.} and Angelo Gallo and Dhiman Ghosh and Francisco Gomes-Neto and Oksana Gorbatyuk and Bing Hao and Vilius Kurauskas and Lauriane Lecoq and Yunfeng Li and Mebus-Antunes, {Nathane Cunha} and Miguel Mompean and Neves-Martins, {Thais Cristtina} and Marti Ninot-Pedrosa and Pinheiro, {Anderson S.} and Letizia Pontoriero and Yulia Pustovalova and Roland Riek and Robertson, {Angus J.} and Saad, {Marie Jose Abi} and Trevino, {Miguel A.} and Tsika, {Aikaterini C.} and Almeida, {Fabio C. L.} and Ad Bax and Katherine Henzler-Wildman and Hoch, {Jeffrey C.} and Kristaps Jaudzems and Douglas Laurents and Julien Orts and Roberta Pierattelli and Spyroulias, {Georgios A.} and Elke Duchardt-Ferner and Jan Ferner and Boris F{\"u}rtig and Martin Hengesbach and Frank Lohr and Nusrat Qureshi and Christian Richter and Krishna Saxena and Andreas Schlundt and Sridhar Sreeramulu and Anna Wacker and Weigand, {Julia E.} and Julia Wirmer-Bartoschek and Jens Wohnert and Harald Schwalbe",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.",

year = "2022",

month = nov,

day = "14",

doi = "10.1002/anie.202205858",

language = "English",

volume = "61",

journal = "Angewandte Chemie (International Edition)",

issn = "1433-7851",

publisher = "WILEY-V C H VERLAG GMBH",

number = "46",

}

Berg, H, Martin, MAW, Altincekic, N, Alshamleh, I, Bains, JK, Blechar, J, Ceylan, B, de Jesus, V, Dhamotharan, K, Fuks, C, Gande, SL, Hargittay, B, Hohmann, KF, Hutchison, MT, Korn, SM, Krishnathas, R, Kutz, F, Linhard, V, Matzel, T, Meiser, N, Niesteruk, A, Pyper, DJ, Schulte, L, Trucks, S, Azzaoui, K, Blommers, MJJ, Gadiya, Y, Karki, R, Zaliani, A, Gribbon, P, Almeida, MDS, Anobom, CD, Bula, AL, Butikofer, M, Caruso, IP, Felli, IC, Da Poian, AT, de Amorim, GC, Fourkiotis, NK, Gallo, A, Ghosh, D, Gomes-Neto, F, Gorbatyuk, O, Hao, B, Kurauskas, V, Lecoq, L, Li, Y, Mebus-Antunes, NC, Mompean, M, Neves-Martins, TC, Ninot-Pedrosa, M, Pinheiro, AS, Pontoriero, L, Pustovalova, Y, Riek, R, Robertson, AJ, Saad, MJA, Trevino, MA, Tsika, AC, Almeida, FCL, Bax, A, Henzler-Wildman, K, Hoch, JC, Jaudzems, K, Laurents, D, Orts, J, Pierattelli, R, Spyroulias, GA, Duchardt-Ferner, E, Ferner, J, Fürtig, B, Hengesbach, M, Lohr, F, Qureshi, N, Richter, C, Saxena, K, Schlundt, A, Sreeramulu, S, Wacker, A, Weigand, JE, Wirmer-Bartoschek, J, Wohnert, J & Schwalbe, H 2022, 'Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development', Angewandte Chemie International Edition, vol. 61, no. 46, e202205858. https://doi.org/10.1002/anie.202205858

TY - JOUR

T1 - Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development

AU - Berg, Hannes

AU - Martin, Maria A. Wirtz

AU - Altincekic, Nadide

AU - Alshamleh, Islam

AU - Bains, Jasleen Kaur

AU - Blechar, Julius

AU - Ceylan, Betul

AU - de Jesus, Vanessa

AU - Dhamotharan, Karthikeyan

AU - Fuks, Christin

AU - Gande, Santosh L.

AU - Hargittay, Bruno

AU - Hohmann, Katharina F.

AU - Hutchison, Marie T.

AU - Korn, Sophie Marianne

AU - Krishnathas, Robin

AU - Kutz, Felicitas

AU - Linhard, Verena

AU - Matzel, Tobias

AU - Meiser, Nathalie

AU - Niesteruk, Anna

AU - Pyper, Dennis J.

AU - Schulte, Linda

AU - Trucks, Sven

AU - Azzaoui, Kamal

AU - Blommers, Marcel J. J.

AU - Gadiya, Yojana

AU - Karki, Reagon

AU - Zaliani, Andrea

AU - Gribbon, Philip

AU - Almeida, Marcius da Silva

AU - Anobom, Cristiane Dinis

AU - Bula, Anna L.

AU - Butikofer, Matthias

AU - Caruso, Icaro Putinhon

AU - Felli, Isabella Caterina

AU - Da Poian, Andrea T.

AU - de Amorim, Gisele Cardoso

AU - Fourkiotis, Nikolaos K.

AU - Gallo, Angelo

AU - Ghosh, Dhiman

AU - Gomes-Neto, Francisco

AU - Gorbatyuk, Oksana

AU - Hao, Bing

AU - Kurauskas, Vilius

AU - Lecoq, Lauriane

AU - Li, Yunfeng

AU - Mebus-Antunes, Nathane Cunha

AU - Mompean, Miguel

AU - Neves-Martins, Thais Cristtina

AU - Ninot-Pedrosa, Marti

AU - Pinheiro, Anderson S.

AU - Pontoriero, Letizia

AU - Pustovalova, Yulia

AU - Riek, Roland

AU - Robertson, Angus J.

AU - Saad, Marie Jose Abi

AU - Trevino, Miguel A.

AU - Tsika, Aikaterini C.

AU - Almeida, Fabio C. L.

AU - Bax, Ad

AU - Henzler-Wildman, Katherine

AU - Hoch, Jeffrey C.

AU - Jaudzems, Kristaps

AU - Laurents, Douglas

AU - Orts, Julien

AU - Pierattelli, Roberta

AU - Spyroulias, Georgios A.

AU - Duchardt-Ferner, Elke

AU - Ferner, Jan

AU - Fürtig, Boris

AU - Hengesbach, Martin

AU - Lohr, Frank

AU - Qureshi, Nusrat

AU - Richter, Christian

AU - Saxena, Krishna

AU - Schlundt, Andreas

AU - Sreeramulu, Sridhar

AU - Wacker, Anna

AU - Weigand, Julia E.

AU - Wirmer-Bartoschek, Julia

AU - Wohnert, Jens

AU - Schwalbe, Harald

PY - 2022/11/14

Y1 - 2022/11/14

N2 - 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.

AB - 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.

KW - COVID19-NMR

KW - Drug Discovery

KW - Fragment Screening

KW - NMR Spectroscopy

KW - Protein

KW - SARS-CoV-2

KW - SMALL-MOLECULE INHIBITORS

KW - ANTIVIRAL COMPOUNDS

KW - CORONAVIRUS

KW - DISCOVERY

KW - FEATURES

KW - OMICRON

UR - http://www.scopus.com/inward/record.url?scp=85139756352&partnerID=8YFLogxK

U2 - 10.1002/anie.202205858

DO - 10.1002/anie.202205858

M3 - Article

VL - 61

JO - Angewandte Chemie (International Edition)

JF - Angewandte Chemie (International Edition)

SN - 1433-7851

IS - 46

M1 - e202205858

ER -

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

Abstract

Austrian Fields of Science 2012

Keywords

UN SDGs

Access to Document

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