tetano
Editor, Senior Moderator
Science
. 2021 Apr 2;eabf7945.
doi: 10.1126/science.abf7945. Online ahead of print.
X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease
Sebastian G?nther[SUP] #[/SUP][SUP] 1 [/SUP], Patrick Y A Reinke[SUP] #[/SUP][SUP] 2 [/SUP], Yaiza Fern?ndez-Garc?a[SUP] 3 [/SUP], Julia Lieske[SUP] 2 [/SUP], Thomas J Lane[SUP] 2 [/SUP], Helen M Ginn[SUP] 4 [/SUP], Faisal H M Koua[SUP] 2 [/SUP], Christiane Ehrt[SUP] 5 [/SUP], Wiebke Ewert[SUP] 2 [/SUP], Dominik Oberthuer[SUP] 2 [/SUP], Oleksandr Yefanov[SUP] 2 [/SUP], Susanne Meier[SUP] 6 7 [/SUP], Kristina Lorenzen[SUP] 8 [/SUP], Boris Krichel[SUP] 9 [/SUP], Janine-Denise Kopicki[SUP] 9 [/SUP], Luca Gelisio[SUP] 2 [/SUP], Wolfgang Brehm[SUP] 2 [/SUP], Ilona Dunkel[SUP] 10 [/SUP], Brandon Seychell[SUP] 11 [/SUP], Henry Gieseler[SUP] 6 7 [/SUP], Brenna Norton-Baker[SUP] 12 13 [/SUP], Beatriz Escudero-P?rez[SUP] 3 [/SUP], Martin Domaracky[SUP] 2 [/SUP], Sofiane Saouane[SUP] 14 [/SUP], Alexandra Tolstikova[SUP] 2 [/SUP], Thomas A White[SUP] 2 [/SUP], Anna H?nle[SUP] 2 [/SUP], Michael Groessler[SUP] 2 [/SUP], Holger Fleckenstein[SUP] 2 [/SUP], Fabian Trost[SUP] 2 [/SUP], Marina Galchenkova[SUP] 2 [/SUP], Yaroslav Gevorkov[SUP] 2 15 [/SUP], Chufeng Li[SUP] 2 [/SUP], Salah Awel[SUP] 2 [/SUP], Ariana Peck[SUP] 16 [/SUP], Miriam Barthelmess[SUP] 2 [/SUP], Frank Schluenzen[SUP] 2 [/SUP], Paulraj Lourdu Xavier[SUP] 2 12 [/SUP], Nadine Werner[SUP] 17 [/SUP], Hina Andaleeb[SUP] 17 [/SUP], Najeeb Ullah[SUP] 17 [/SUP], Sven Falke[SUP] 17 [/SUP], Vasundara Srinivasan[SUP] 17 [/SUP], Bruno Alves Fran?a[SUP] 17 [/SUP], Martin Schwinzer[SUP] 17 [/SUP], H?vila Brognaro[SUP] 17 [/SUP], Cromarte Rogers[SUP] 6 7 [/SUP], Diogo Melo[SUP] 6 7 [/SUP], Joanna J Zaitseva-Doyle[SUP] 6 7 [/SUP], Juraj Knoska[SUP] 2 [/SUP], Gisel E Pe?a-Murillo[SUP] 2 [/SUP], Aida Rahmani Mashhour[SUP] 2 [/SUP], Vincent Hennicke[SUP] 2 [/SUP], Pontus Fischer[SUP] 2 [/SUP], Johanna Hakanp??[SUP] 14 [/SUP], Jan Meyer[SUP] 14 [/SUP], Philip Gribbon[SUP] 18 [/SUP], Bernhard Ellinger[SUP] 18 [/SUP], Maria Kuzikov[SUP] 18 [/SUP], Markus Wolf[SUP] 18 [/SUP], Andrea R Beccari[SUP] 19 [/SUP], Gleb Bourenkov[SUP] 20 [/SUP], David von Stetten[SUP] 20 [/SUP], Guillaume Pompidor[SUP] 20 [/SUP], Isabel Bento[SUP] 20 [/SUP], Saravanan Panneerselvam[SUP] 20 [/SUP], Ivars Karpics[SUP] 20 [/SUP], Thomas R Schneider[SUP] 20 [/SUP], Maria Marta Garcia-Alai[SUP] 20 [/SUP], Stephan Niebling[SUP] 20 [/SUP], Christian G?nther[SUP] 20 [/SUP], Christina Schmidt[SUP] 8 [/SUP], Robin Schubert[SUP] 8 [/SUP], Huijong Han[SUP] 8 [/SUP], Juliane Boger[SUP] 21 [/SUP], Diana C F Monteiro[SUP] 22 [/SUP], Linlin Zhang[SUP] 21 23 [/SUP], Xinyuanyuan Sun[SUP] 21 23 [/SUP], Jonathan Pletzer-Zelgert[SUP] 5 [/SUP], Jan Wollenhaupt[SUP] 24 [/SUP], Christian G Feiler[SUP] 24 [/SUP], Manfred S Weiss[SUP] 24 [/SUP], Eike-Christian Schulz[SUP] 12 [/SUP], Pedram Mehrabi[SUP] 12 [/SUP], Katarina Karni?ar[SUP] 25 26 [/SUP], Aleksandra Usenik[SUP] 25 26 [/SUP], Jure Loboda[SUP] 25 [/SUP], Henning Tidow[SUP] 6 27 [/SUP], Ashwin Chari[SUP] 28 [/SUP], Rolf Hilgenfeld[SUP] 21 23 [/SUP], Charlotte Uetrecht[SUP] 9 [/SUP], Russell Cox[SUP] 29 [/SUP], Andrea Zaliani[SUP] 18 [/SUP], Tobias Beck[SUP] 6 11 [/SUP], Matthias Rarey[SUP] 5 [/SUP], Stephan G?nther[SUP] 3 [/SUP], Dusan Turk[SUP] 25 26 [/SUP], Winfried Hinrichs[SUP] 17 30 [/SUP], Henry N Chapman[SUP] 2 6 31 [/SUP], Arwen R Pearson[SUP] 6 7 [/SUP], Christian Betzel[SUP] 6 17 [/SUP], Alke Meents[SUP] 1 [/SUP]
Affiliations
Abstract
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M[SUP]pro[/SUP]), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M[SUP]pro[/SUP] In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.
. 2021 Apr 2;eabf7945.
doi: 10.1126/science.abf7945. Online ahead of print.
X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease
Sebastian G?nther[SUP] #[/SUP][SUP] 1 [/SUP], Patrick Y A Reinke[SUP] #[/SUP][SUP] 2 [/SUP], Yaiza Fern?ndez-Garc?a[SUP] 3 [/SUP], Julia Lieske[SUP] 2 [/SUP], Thomas J Lane[SUP] 2 [/SUP], Helen M Ginn[SUP] 4 [/SUP], Faisal H M Koua[SUP] 2 [/SUP], Christiane Ehrt[SUP] 5 [/SUP], Wiebke Ewert[SUP] 2 [/SUP], Dominik Oberthuer[SUP] 2 [/SUP], Oleksandr Yefanov[SUP] 2 [/SUP], Susanne Meier[SUP] 6 7 [/SUP], Kristina Lorenzen[SUP] 8 [/SUP], Boris Krichel[SUP] 9 [/SUP], Janine-Denise Kopicki[SUP] 9 [/SUP], Luca Gelisio[SUP] 2 [/SUP], Wolfgang Brehm[SUP] 2 [/SUP], Ilona Dunkel[SUP] 10 [/SUP], Brandon Seychell[SUP] 11 [/SUP], Henry Gieseler[SUP] 6 7 [/SUP], Brenna Norton-Baker[SUP] 12 13 [/SUP], Beatriz Escudero-P?rez[SUP] 3 [/SUP], Martin Domaracky[SUP] 2 [/SUP], Sofiane Saouane[SUP] 14 [/SUP], Alexandra Tolstikova[SUP] 2 [/SUP], Thomas A White[SUP] 2 [/SUP], Anna H?nle[SUP] 2 [/SUP], Michael Groessler[SUP] 2 [/SUP], Holger Fleckenstein[SUP] 2 [/SUP], Fabian Trost[SUP] 2 [/SUP], Marina Galchenkova[SUP] 2 [/SUP], Yaroslav Gevorkov[SUP] 2 15 [/SUP], Chufeng Li[SUP] 2 [/SUP], Salah Awel[SUP] 2 [/SUP], Ariana Peck[SUP] 16 [/SUP], Miriam Barthelmess[SUP] 2 [/SUP], Frank Schluenzen[SUP] 2 [/SUP], Paulraj Lourdu Xavier[SUP] 2 12 [/SUP], Nadine Werner[SUP] 17 [/SUP], Hina Andaleeb[SUP] 17 [/SUP], Najeeb Ullah[SUP] 17 [/SUP], Sven Falke[SUP] 17 [/SUP], Vasundara Srinivasan[SUP] 17 [/SUP], Bruno Alves Fran?a[SUP] 17 [/SUP], Martin Schwinzer[SUP] 17 [/SUP], H?vila Brognaro[SUP] 17 [/SUP], Cromarte Rogers[SUP] 6 7 [/SUP], Diogo Melo[SUP] 6 7 [/SUP], Joanna J Zaitseva-Doyle[SUP] 6 7 [/SUP], Juraj Knoska[SUP] 2 [/SUP], Gisel E Pe?a-Murillo[SUP] 2 [/SUP], Aida Rahmani Mashhour[SUP] 2 [/SUP], Vincent Hennicke[SUP] 2 [/SUP], Pontus Fischer[SUP] 2 [/SUP], Johanna Hakanp??[SUP] 14 [/SUP], Jan Meyer[SUP] 14 [/SUP], Philip Gribbon[SUP] 18 [/SUP], Bernhard Ellinger[SUP] 18 [/SUP], Maria Kuzikov[SUP] 18 [/SUP], Markus Wolf[SUP] 18 [/SUP], Andrea R Beccari[SUP] 19 [/SUP], Gleb Bourenkov[SUP] 20 [/SUP], David von Stetten[SUP] 20 [/SUP], Guillaume Pompidor[SUP] 20 [/SUP], Isabel Bento[SUP] 20 [/SUP], Saravanan Panneerselvam[SUP] 20 [/SUP], Ivars Karpics[SUP] 20 [/SUP], Thomas R Schneider[SUP] 20 [/SUP], Maria Marta Garcia-Alai[SUP] 20 [/SUP], Stephan Niebling[SUP] 20 [/SUP], Christian G?nther[SUP] 20 [/SUP], Christina Schmidt[SUP] 8 [/SUP], Robin Schubert[SUP] 8 [/SUP], Huijong Han[SUP] 8 [/SUP], Juliane Boger[SUP] 21 [/SUP], Diana C F Monteiro[SUP] 22 [/SUP], Linlin Zhang[SUP] 21 23 [/SUP], Xinyuanyuan Sun[SUP] 21 23 [/SUP], Jonathan Pletzer-Zelgert[SUP] 5 [/SUP], Jan Wollenhaupt[SUP] 24 [/SUP], Christian G Feiler[SUP] 24 [/SUP], Manfred S Weiss[SUP] 24 [/SUP], Eike-Christian Schulz[SUP] 12 [/SUP], Pedram Mehrabi[SUP] 12 [/SUP], Katarina Karni?ar[SUP] 25 26 [/SUP], Aleksandra Usenik[SUP] 25 26 [/SUP], Jure Loboda[SUP] 25 [/SUP], Henning Tidow[SUP] 6 27 [/SUP], Ashwin Chari[SUP] 28 [/SUP], Rolf Hilgenfeld[SUP] 21 23 [/SUP], Charlotte Uetrecht[SUP] 9 [/SUP], Russell Cox[SUP] 29 [/SUP], Andrea Zaliani[SUP] 18 [/SUP], Tobias Beck[SUP] 6 11 [/SUP], Matthias Rarey[SUP] 5 [/SUP], Stephan G?nther[SUP] 3 [/SUP], Dusan Turk[SUP] 25 26 [/SUP], Winfried Hinrichs[SUP] 17 30 [/SUP], Henry N Chapman[SUP] 2 6 31 [/SUP], Arwen R Pearson[SUP] 6 7 [/SUP], Christian Betzel[SUP] 6 17 [/SUP], Alke Meents[SUP] 1 [/SUP]
Affiliations
- PMID: 33811162
- DOI: 10.1126/science.abf7945
Abstract
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M[SUP]pro[/SUP]), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M[SUP]pro[/SUP] In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.