Ashwin Chari

Max Planck Institute for Biophysical Chemistry

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Rolf Hilgenfeld

University of Lübeck

Arwen R. Pearson

Universität Hamburg

F. Koua

Deutsches Elektronen-Synchrotron DESY

C. Feiler

Helmholtz-Zentrum Berlin für Materialien und Energie

B. Alves Franca

Universität Hamburg

M. Galchenkova

Center for Free-Electron Laser Science

V. Hennicke

Universität Hamburg

J. Pletzer-Zelgert

Universität Hamburg

M. Domaracký

Center for Free-Electron Laser Science

Henning Tidow

Universität Hamburg

Cooperative Institutions

Universität Hamburg

Deutsches Elektronen-Synchrotron DESY

Max Planck Institute for Biophysical Chemistry

Center for Free-Electron Laser Science

University of Göttingen

Max Planck Institute for Multidisciplinary Sciences

Max Planck Society

University of Würzburg

Max Planck Institute for the Structure and Dynamics of Matter

European Molecular Biology Laboratory

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Reconstitution of the human U sn RNP assembly machinery reveals stepwise Sm protein organization

The EMBO Journal (2015)

Nils Neuenkirchen Clemens Englbrecht Jürgen Ohmer Thomas Ziegenhals Ashwin Chari

10.15252/embj.201490350

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Citations (53)

Structural and Functional Analyses of the Human PDH Complex Suggest a “Division-of-Labor” Mechanism by Local E1 and E3 Clusters

Structure (2019)

Sabin Prajapati David Haselbach Sabine Wittig Mulchand S. Patel Ashwin Chari

10.1016/j.str.2019.04.009

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Citations (28)

Structure of SARS-CoV-2 Main Protease bound to TH-302.

S. Guenther P. Reinke D. Oberthüer Oleksandr Yefanov Luca Gelisio

2019-20 coronavirus outbreak

Coronavirus

Pandemic

10.2210/pdb7aws/pdb

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Citations (0)

Structure of SARS-CoV-2 Main Protease bound to Fusidic Acid.

S. Guenther P. Reinke D. Oberthüer Oleksandr Yefanov Luca Gelisio

Fusidic acid

2019-20 coronavirus outbreak

10.2210/pdb7a1u/pdb

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Citations (0)

Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design

Nature Communications (2024)

Lisa-Marie Funk Gereon Poschmann Fabian Rabe von Pappenheim Ashwin Chari Kim M. Stegmann

Abstract Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The SARS-CoV-2 main protease (M pro ), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M pro is subject to redox regulation in vitro and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include a disulfide-dithiol switch between the catalytic cysteine C145 and cysteine C117, and generation of an allosteric cysteine-lysine-cysteine SONOS bridge that is required for structural stability under oxidative stress conditions, such as those exerted by the innate immune system. We identify homo- and heterobifunctional reagents that mimic the redox switching and inhibit M pro activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS-CoV and SARS-CoV, indicating their potential as common druggable sites.

Druggability

Cysteine protease

10.1038/s41467-023-44621-0

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Citations (14)

Structure of SARS-CoV-2 Main Protease bound to Tegafur

S. Guenther P. Reinke D. Oberthüer Oleksandr Yefanov Luca Gelisio

2019-20 coronavirus outbreak

10.2210/pdb7awr/pdb

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Citations (0)

Multiple redox switches of the SARS-CoV-2 main protease in vitro provide new opportunities for drug design

Research Square (Research Square) (2022)

Kai Tittmann Lisa-Marie Funk Fabian Rabe von Pappenheim Marie Wensien Nora Eulig

Abstract Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for stopping the current COVID-19 pandemic and preventing future outbreaks. The SARS-CoV-2 main protease (M pro ), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M pro is subject to redox regulation in vitro and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include a disulfide-dithiol switch between the catalytic cysteine C145 and cysteine C117, and generation of an allosteric cysteine-lysine-cysteine SONOS bridge that is required for structural stability under oxidative stress conditions, such as those exerted by the innate immune system. We identify homo- and heterobifunctional reagents that mimic the redox switching and inhibit M pro activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS-CoV and SARS-CoV, indicating their potential as common druggable sites.

Druggability

Cysteine protease

Drug Development

10.21203/rs.3.rs-2341326/v1

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Citations (4)

LSm1-7 complexes bind to specific sites in viral RNA genomes and regulate their translation and replication

RNA (2010)

Rui Pedro Galão Ashwin Chari Isabel Alves‐Rodrigues Daniela Lobão Antonio Más

LSm1-7 complexes promote cellular mRNA degradation, in addition to translation and replication of positive-strand RNA viruses such as the Brome mosaic virus (BMV). Yet, how LSm1-7 complexes act on their targets remains elusive. Here, we report that reconstituted recombinant LSm1-7 complexes directly bind to two distinct RNA-target sequences in the BMV genome, a tRNA-like structure at the 3'-untranslated region and two internal A-rich single-stranded regions. Importantly, in vivo analysis shows that these sequences regulate the translation and replication of the BMV genome. Furthermore, both RNA-target sequences resemble those found for Hfq, the LSm counterpart in bacteria, suggesting conservation through evolution. Our results provide the first evidence that LSm1-7 complexes interact directly with viral RNA genomes and open new perspectives in the understanding of LSm1-7 functions.

Brome mosaic virus

10.1261/rna.1712910

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Citations (43)

Structure of SARS-CoV-2 Main Protease bound to pyrithione zinc

S. Guenther P. Reinke D. Oberthüer Oleksandr Yefanov Luca Gelisio

2019-20 coronavirus outbreak

10.2210/pdb6yt8/pdb

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Citations (0)

Structure of SARS-CoV-2 Main Protease bound to Tretazicar.

S. Guenther P. Reinke D. Oberthüer Oleksandr Yefanov Luca Gelisio

2019-20 coronavirus outbreak

10.2210/pdb7ak4/pdb

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Citations (0)