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

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 in Portuguese

Triagem abrangente de fragmentos do SARS-CoV-2
Proteome - novo espaço químico
Desenvolvimento de medicamentos

Keywords

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

Publisher

Wiley-VCH

Citation

BERG, Hannes et al. Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development. Angew. Chem. Int. Ed., 2022, e202205858.

DOI

10.1002/anie.202205858

ISSN

1521-3773

Notes

Francisco Gomes Neto - Fundação 0swaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxinologia. Rio de Janeiro, RJ, Brasil. Demais Autores: Hannes Berg,[a,b‡] Maria A. Wirtz Martin,[a,b‡] Nadide Altincekic,[a,b‡] Islam Alshamleh,[a,b] Jasleen Kaur Bains,[a,b] Julius Blechar,[a] Betül Ceylan,[a,b] Vanessa de Jesus,[a,b] Karthikeyan Dhamotharan,[b,c] Christin Fuks,[a] Santosh L. Gande,[a,b] Bruno Hargittay,[a,b] Katharina F. Hohmann,[a,b] Marie T. Hutchison,[a,b] Sophie Marianne Korn,[b,c] Robin Krishnathas,[a,b] Felicitas Kutz,[a,b] Verena Linhard,[a,b] Tobias Matzel,[a,b] Nathalie Meiser,[a] Anna Niesteruk,[a,b] Dennis J. Pyper,[a,b] Linda Schulte,[a,b] Sven Trucks,[a] Kamal Azzaoui,[d] Marcel J. J. Blommers,[d] Yojana Gadiya,[e,f] Reagon Karki,[e,f] Andrea Zaliani,[e,f] Philip Gribbon,[e,f] Marcius da Silva Almeida,[g,h] Cristiane Dinis Anobom,[i,j] Anna L. Bula,[k] Matthias Bütikofer,[l] Ícaro Putinhon Caruso,[g,m] Isabella Caterina Felli,[n,o] Andrea T. Da Poian,[g] Gisele Cardoso de Amorim,[g,p] Nikolaos K. Fourkiotis,[q] Angelo Gallo,[q,r] Dhiman Ghosh, i,s] Oksana Gorbatyuk,[t] Bing Hao,[t] Vilius Kurauskas,[u] Lauriane Lecoq,[v] Yunfeng Li,[t] Nathane Cunha Mebus-Antunes,[g] Miguel Mompeán,[w] Thais Cristtina Neves-Martins,[g] Martí Ninot-Pedrosa,[v] Anderson S. Pinheiro,[j] Letizia Pontoriero,[n,o] Yulia Pustovalova,[t] Roland Riek,[l] Angus J. Robertson,[x] Marie Jose Abi Saad,[y] Miguel Á. Treviño,[w] Aikaterini C. Tsika,[q] Fabio C. L. Almeida,[g,i] Ad Bax,[x] Katherine Henzler-Wildman,[u] Jeffrey C. Hoch,[t] Kristaps Jaudzems,[k] Douglas V. Laurents,[w] Julien Orts,[y] Roberta Pierattelli,[n,o] Georgios A. Spyroulias,[q] Elke Duchardt-Ferner,[b,c] Jan Ferner,[a,b] Boris Fürtig,[a,b] Martin Hengesbach,[a] Frank Löhr,[b,c] Nusrat Qureshi,[a,b] Christian Richter,[a,b] Krishna Saxena,[a,b] Andreas Schlundt,[b,c] Sridhar Sreeramulu,[a,b] Anna Wacker,[a,b] Julia E. Weigand,[z] Julia Wirmer-Bartoschek,[a,b] Jens Wöhnert,[b,c] and Harald Schwalbe*[a,b]. Notas- Instituições: [a,b] H. Berg[‡], M. A. Wirtz Martin[‡], N. Altincekic[‡], Dr. I. Alshamleh, J. K. Bains, J. Blechar, B. Ceylan, V. de Jesus, C. Fuks, Dr. S. L. Gande, B. Hargittay, K. F. Hohmann, M. T. Hutchison, R. Krishnathas, F. Kutz, V. Linhard, T. Matzel, N. Meiser, Dr. A. Niesteruk, D. J. Pyper, Dr. L. Schulte, Dr. S. Trucks, Dr. J. Ferner, Dr. B. Fürtig, Dr. M. Hengesbach, Dr. N. Qureshi, Dr. C. Richter, Dr. K. Saxena, Dr. S. Sreeramulu, Dr. A. Wacker, Dr. J. Wirmer-Bartoschek, Dr. Prof. Dr. H. Schwalbe [a] Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt, Frankfurt am Main, Germany [b] Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Frankfurt am Main, Germany Max-von-LaueStrasse 7+9, 60438 Frankfurt am Main (Germany) E-mail: schwalbe@nmr.uni-frankfurt.de [b,c] K. Dhamotharan, Dr. S. M. Korn, Dr. E. Duchardt-Ferner, Dr. F. Löhr, Dr. A. Schlundt, Prof. Dr. J. Wöhnert [c] Institute for Molecular Biosciences, Goethe University Frankfurt, Frankfurt am Main, Germany Max-von-Laue Strasse 7+9, 60438 Frankfurt am Main (Germany) [d] Dr. K. Azzaoui, Dr. M. J. J. Blommers Saverna Therapeutics, Pumpmattenweg 3, 4105 Biel-Benken, Switzerland [e,f] Y. Gadiya, R. Karki, A. Zaliani, Dr. P. Gribbon [e] Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Screening Port, Schnackenburgallee 114, 22525 Hamburg, Germany [f] Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany [g,h] M. S. Almeida, A. T. Da Poian, N. C. Mebus-Antunes, T. C. Neves-Martins, F. C. L. Almeida [g] Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil [h] Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany [i,j] C. D Anobom, A. S. Pinheiro [i] National Center of Nuclear Magnetic Resonance (CNRMN), CENABIO, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil [j] Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil [k] A. L. Bula, K. Jaudzems [k] Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia [l] M. Bütikofer, D. Ghosh, R. Riek [l] ETH, Swiss Federal Institute of Technology, Laboratory of Physical Chemistry, HCI F217, Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland. [g,m] Í. P. Caruso [m] Multiuser Center for Biomolecular Innovation (CMIB), Department of Physics, São Paulo State University (UNESP), São José do Rio Preto, Brazil [n,o] I. C. Felli, L. Pontoriero, R. Pierattelli [n] Magnetic Resonance Center (CERM), University of Florence, Via Luigi Sacconi 6, Sesto Fiorentino, 50019, Florence, Italy [o] Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, Sesto Fiorentino, 50019, Florence, Italy [g,p] G. C. de Amorim [p] Multidisciplinary Center for Research in Biology (NUMPEX), Campus Duque de Caxias Federal University of Rio de Janeiro, Duque de Caxias, Brazil [q] N. K. Fourkiotis, A. C. Tsika, G. A. Spyroulias [q] Department of Pharmacy, University of Patras, Patras, Greece [q,r] A. Gallo, [r] Department of Chemistry, University of Torino IT -10126 Torino. Italy [i,s] F. Gomes-Neto [s] Laboratory of Toxinology, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil [t] O. Gorbatyuk, B. Hao, Y. Li, Y. Pustovalova, J. C. Hoch [t] Department of Molecular Biology and Biophysics UConn Health 263 Farmington Ave., Farmington, CT 06030-3305 USA [u] V. Kurauskas, K. Henzler-Wildman [u] Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706 [v] L. Lecoq, M. Ninot-Pedrosa [v] Molecular Microbiology and Structural Biochemistry, UMR5086 CNRS/Université Lyon 1, 7, passage du Vercors, 69367 Lyon, France.

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/58051

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