RT Journal Article
SR Electronic
T1 Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.12.378422
DO 10.1101/2020.11.12.378422
A1 Sebastian Günther
A1 Patrick Y. A. Reinke
A1 Yaiza Fernández-García
A1 Julia Lieske
A1 Thomas J. Lane
A1 Helen Ginn
A1 Faisal H. M. Koua
A1 Christiane Ehrt
A1 Wiebke Ewert
A1 Dominik Oberthuer
A1 Oleksandr Yefanov
A1 Susanne Meier
A1 Kristina Lorenzen
A1 Boris Krichel
A1 Janine-Denise Kopicki
A1 Luca Gelisio
A1 Wolfgang Brehm
A1 Ilona Dunkel
A1 Brandon Seychell
A1 Henry Gieseler
A1 Brenna Norton-Baker
A1 Beatriz Escudero-Pérez
A1 Martin Domaracky
A1 Sofiane Saouane
A1 Alexandra Tolstikova
A1 Thomas A. White
A1 Anna Hänle
A1 Michael Groessler
A1 Holger Fleckenstein
A1 Fabian Trost
A1 Marina Galchenkova
A1 Yaroslav Gevorkov
A1 Chufeng Li
A1 Salah Awel
A1 Ariana Peck
A1 Miriam Barthelmess
A1 Frank Schlünzen
A1 P. Lourdu Xavier
A1 Nadine Werner
A1 Hina Andaleeb
A1 Najeeb Ullah
A1 Sven Falke
A1 Vasundara Srinivasan
A1 Bruno Alves Franca
A1 Martin Schwinzer
A1 Hévila Brognaro
A1 Cromarte Rogers
A1 Diogo Melo
A1 Jo J. Zaitsev-Doyle
A1 Juraj Knoska
A1 Gisel E. Peña Murillo
A1 Aida Rahmani Mashhour
A1 Filip Guicking
A1 Vincent Hennicke
A1 Pontus Fischer
A1 Johanna Hakanpää
A1 Jan Meyer
A1 Phil Gribbon
A1 Bernhard Ellinger
A1 Maria Kuzikov
A1 Markus Wolf
A1 Gleb Borenkov
A1 David von Stetten
A1 Guillaume Pompidor
A1 Isabel Bento
A1 Saravanan Panneerselvam
A1 Ivars Karpics
A1 Thomas R. Schneider
A1 Maria Marta Garcia Alai
A1 Stephan Niebling
A1 Christian Günther
A1 Christina Schmidt
A1 Robin Schubert
A1 Huijong Han
A1 Juliane Boger
A1 Diana C. F. Monteiro
A1 Linlin Zhang
A1 Xinyuanyuan Sun
A1 Jonathan Pletzer-Zelgert
A1 Jan Wollenhaupt
A1 Christian G. Feiler
A1 Manfred S. Weiss
A1 Eike-Christian Schulz
A1 Pedram Mehrabi
A1 Katarina Karničar
A1 Aleksandra Usenik
A1 Jure Loboda
A1 Henning Tidow
A1 Ashwin Chari
A1 Rolf Hilgenfeld
A1 Charlotte Uetrecht
A1 Russell Cox
A1 Andrea Zaliani
A1 Tobias Beck
A1 Matthias Rarey
A1 Stephan Günther
A1 Dusan Turk
A1 Winfried Hinrichs
A1 Henry N. Chapman
A1 Arwen R. Pearson
A1 Christian Betzel
A1 Alke Meents
YR 2020
UL http://biorxiv.org/content/early/2020/11/12/2020.11.12.378422.abstract
AB The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of repurposing drug libraries1 containing 5953 individual compounds against the SARS-CoV-2 main protease (Mpro), which is a potent drug target as it is essential for the virus replication2. 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 binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. Interestingly, two compounds bind outside the active site to the native dimer interface in close proximity to the S1 binding pocket. Another compound binds in a cleft between the catalytic and dimerization domain of Mpro. Neither binding site is related to the enzymatic active site and both represent attractive targets for drug development against SARS-CoV-2. This X-ray screening approach thus has the potential to help deliver an approved drug on an accelerated time-scale for this and future pandemics3.Competing Interest StatementThe authors have declared no competing interest.