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Journal/Book: Angew. Chem. Chem. Ed. Engl.
Published: 2022
Pages: e202205858
Volume: 61
Issue: 46
Accession no.:
Publisher:
ISBN:

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

Berg H, Wirtz Martin M A, Altincekic N, Alshamleh I, Bains K J, Blechar J, Ceylan B, de Jesus V, Dhamotharan K, Fuks C, Gande S L, Hargittay B, Hohmann K F, Hutchinson M T, Korn S M, Krishnathas R, Kutz F, Linhard V, Matzel T, Meiser N, Niesteruk A, Pyper D J, Schulte L, Trucks S, Azzaoui K, Blommers M J J, Gadiya Y, Karki R, Zaliani A, Gribbon P, da Silva Almeida M, Anobom C D, Bula A L, Bütikofer M, Putinhon Caruso I, Felli I C, Da Poian A T, Cardoso de Amorim G, Fourkiotis N K, Gallo A, Ghosh D, Gomes-Neto F, Gorbatyk O, Hao B, Kuraukas V, Lecoq L, Li Y, Mebus-Antunes N C, Mompean M, Neves-Martins T C, Ninot-Pedrosa M, PinheiroA S, Pontoriero L, Pustovalova Y, Riek R, Robertson A J, Abi Saad M J, Trevino M A, Tsika A C, Almeida F C L, Bax A, Henzler-Wildman K, Hoch J C, Jaudzems K, Laurents D V, Orts J, Pierattelli R, Spyroulias G, Duchardt-Ferner E, Ferner J, Fürtig B, Hengesbach M, Löhr F, Qureshi N, Richter C, Saxena K, Schlundt A, Sreeramulu S, Wacker A, Weigand J E, Wirmer-Bartoschek J, Wöhnert J, Schwalbe H
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.
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Prof. Dr. Harald Schwalbe
Institut für Organische Chemie und Chemische Biologie
Johann Wolfgang Goethe Universität
Max-von-Laue-Str. 7
D-60438 Frankfurt am Main
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