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.

Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development / Berg, Hannes; Wirtz Martin, Maria A; Altincekic, Nadide; Alshamleh, Islam; Kaur Bains, Jasleen; Blechar, Julius; Ceylan, Betül; de Jesus, Vanessa; Dhamotharan, Karthikeyan; Fuks, Christin; Gande, Santosh L; Hargittay, Bruno; Hohmann, Katharina F; Hutchinson, Marie T; Korn, Sophie Marianne; Krishnathas, Robin; Kutz, Felicitas; Linhard, Verena; Matzel, Tobias; Meiser, Nathalie; Niesteruk, Anna; Pyper, Dennis J; Schulte, Linda; Trucks, Sven; Azzaoui, Kamal; Blommers, Marcel J J; Gadiya, Yojana; Karki, Reagon; Zaliani, Andrea; Gribbon, Philip; Almeida, Marcius da Silva; Anobom, Cristiane Dinis; Bula, Anna Lina; Buetikofer, Matthias; Caruso, Ícaro Putinhon; Felli, Isabella Caterina; Da Poian, Andrea T; de Amorim, Gisele Cardoso; Fourkiotis, Nikolaos K; Gallo, Angelo; Ghosh, Dhiman; Gomes-Neto, Francesco; Gorbatyuk, Oksana; Hao, Bing; Kurauskas, Vilius; Lecoq, Lauriane; Li, Yunfeng; Mebus-Antunes, Nathane Cunha; Mompean, Miguel; Neves-Martins, Thais Cristtina; Ninot-Pedrosa, Marti; Pinheiro, Anderson S; Pontoriero, Letizia; Pustovalova, Yulia; Riek, Roland; Robertson, Angus; Abi Saad, Marie Jose; Treviño, Miguel A; Tsika, Aikaterini C; Almeida, Fabio C L; Bax, Ad; Henzler-Wildman, Katherine; Hoch, Jeffrey C; Jaudzems, Kristaps; Laurents, Douglas V; Orts, Julien; Pierattelli, Roberta; Spyroulias, Georgios A; Duchardt-Ferner, Elke; Ferner, Jan; Fuertig, Boris; Hengesbach, Martin; Löhr, Frank; Qureshi, Nusrat; Richter, Christian; Saxena, Krishna; Schlundt, Andreas; Sreeramulu, Sridhar; Wacker, Anna; Weigand, Julia E; Wirmer-Bartoschek, Julia; Woehnert, Jens; Schwalbe, Harald. - In: ANGEWANDTE CHEMIE. - ISSN 1521-3773. - ELETTRONICO. - (2022), pp. 1-13. [10.1002/anie.202205858]

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

Felli, Isabella Caterina;Gallo, Angelo;Pontoriero, Letizia;Pierattelli, Roberta;Schwalbe, Harald
2022

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.
1
13
Berg, Hannes; Wirtz Martin, Maria A; Altincekic, Nadide; Alshamleh, Islam; Kaur Bains, Jasleen; Blechar, Julius; Ceylan, Betül; de Jesus, Vanessa; Dhamotharan, Karthikeyan; Fuks, Christin; Gande, Santosh L; Hargittay, Bruno; Hohmann, Katharina F; Hutchinson, Marie T; Korn, Sophie Marianne; Krishnathas, Robin; Kutz, Felicitas; Linhard, Verena; Matzel, Tobias; Meiser, Nathalie; Niesteruk, Anna; Pyper, Dennis J; Schulte, Linda; Trucks, Sven; Azzaoui, Kamal; Blommers, Marcel J J; Gadiya, Yojana; Karki, Reagon; Zaliani, Andrea; Gribbon, Philip; Almeida, Marcius da Silva; Anobom, Cristiane Dinis; Bula, Anna Lina; Buetikofer, Matthias; Caruso, Ícaro Putinhon; Felli, Isabella Caterina; Da Poian, Andrea T; de Amorim, Gisele Cardoso; Fourkiotis, Nikolaos K; Gallo, Angelo; Ghosh, Dhiman; Gomes-Neto, Francesco; Gorbatyuk, Oksana; Hao, Bing; Kurauskas, Vilius; Lecoq, Lauriane; Li, Yunfeng; Mebus-Antunes, Nathane Cunha; Mompean, Miguel; Neves-Martins, Thais Cristtina; Ninot-Pedrosa, Marti; Pinheiro, Anderson S; Pontoriero, Letizia; Pustovalova, Yulia; Riek, Roland; Robertson, Angus; Abi Saad, Marie Jose; Treviño, Miguel A; Tsika, Aikaterini C; Almeida, Fabio C L; Bax, Ad; Henzler-Wildman, Katherine; Hoch, Jeffrey C; Jaudzems, Kristaps; Laurents, Douglas V; Orts, Julien; Pierattelli, Roberta; Spyroulias, Georgios A; Duchardt-Ferner, Elke; Ferner, Jan; Fuertig, Boris; Hengesbach, Martin; Löhr, Frank; Qureshi, Nusrat; Richter, Christian; Saxena, Krishna; Schlundt, Andreas; Sreeramulu, Sridhar; Wacker, Anna; Weigand, Julia E; Wirmer-Bartoschek, Julia; Woehnert, Jens; Schwalbe, Harald
File in questo prodotto:
File Dimensione Formato  
ANIE-9999-0.pdf

accesso aperto

Tipologia: Pdf editoriale (Version of record)
Licenza: Open Access
Dimensione 1.71 MB
Formato Adobe PDF
1.71 MB Adobe PDF Visualizza/Apri

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1283101
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact