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, Betül Ceylan, Vanessa de Jesus, Karthikeyan Dhamotharan, Christin Fuks, S.L. Gande, Bruno Hargittay, Katharina F. Hohmann, Marie Hutchison, Sophie Marianne Korn, Robin Krishnathas, Felicitas Kutz, V.L. 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 S. Almeida, Cristiane Dinis Anobom, Anna L. Bula, Matthias Bütikofer, Ícaro Putinhon Caruso, Isabella C. 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 C. Mebus-Antunes, Miguel Mompeán, Thais C. Neves-Martins, Martí Ninot‐Pedrosa, Anderson S. Pinheiro, Letizia Pontoriero, Yulia Pustovalova, Roland Riek, Angus J. Robertson, Marie Jose Abi Saad, Miguel Á. Treviño, Aikaterini C. Tsika, Fábio C. L. Almeida, Ad Bax, Katherine A. Henzler‐Wildman, Jeffrey C. Hoch, Kristaps Jaudzems, Douglas V. Laurents, Julien Orts, Roberta Pierattelli, Georgios A. Spyroulias, Elke Duchardt‐Ferner, Jan Ferner, Boris Fürtig, Martin Hengesbach, Frank Löhr, Nusrat S. Qureshi, Christian Richter, Krishna Saxena, Andreas Schlundt, Sridhar Sreeramulu, Anna Wacker, Julia E. Weigand, Julia Wirmer‐Bartoschek, Jens Wöhnert, Harald Schwalbe
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.