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Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant

View ORCID ProfileAnn-Kathrin Reuschl, View ORCID ProfileLucy G. Thorne, View ORCID ProfileLorena Zuliani-Alvarez, View ORCID ProfileMehdi Bouhaddou, View ORCID ProfileKirsten Obernier, View ORCID ProfileMargaret Soucheray, Jane Turner, Jacqueline M. Fabius, Gina T. Nguyen, View ORCID ProfileDanielle L. Swaney, View ORCID ProfileRomel Rosales, View ORCID ProfileKris M. White, Pablo Avilés, View ORCID ProfileIlsa T. Kirby, View ORCID ProfileJames E. Melnyk, View ORCID ProfileYing Shi, View ORCID ProfileZiyang Zhang, View ORCID ProfileKevan M. Shokat, View ORCID ProfileAdolfo García-Sastre, View ORCID ProfileClare Jolly, View ORCID ProfileGregory J. Towers, View ORCID ProfileNevan J. Krogan
doi: https://doi.org/10.1101/2021.01.24.427991
Ann-Kathrin Reuschl
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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  • ORCID record for Ann-Kathrin Reuschl
Lucy G. Thorne
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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  • ORCID record for Lucy G. Thorne
Lorena Zuliani-Alvarez
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Mehdi Bouhaddou
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Kirsten Obernier
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Margaret Soucheray
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Jane Turner
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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Jacqueline M. Fabius
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
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Gina T. Nguyen
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
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Danielle L. Swaney
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Romel Rosales
6Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
7Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Kris M. White
6Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
7Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Pablo Avilés
8PharmaMar, Research and Development Department, 28770 Colmenar Viejo, Madrid, Spain
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Ilsa T. Kirby
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
9Howard Hughes Medical Institute, San Francisco, CA 94158, USA
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James E. Melnyk
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
9Howard Hughes Medical Institute, San Francisco, CA 94158, USA
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Ying Shi
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
9Howard Hughes Medical Institute, San Francisco, CA 94158, USA
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Ziyang Zhang
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
9Howard Hughes Medical Institute, San Francisco, CA 94158, USA
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Kevan M. Shokat
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
9Howard Hughes Medical Institute, San Francisco, CA 94158, USA
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Adolfo García-Sastre
6Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
7Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
10Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
11The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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  • For correspondence: nevan.krogan@ucsf.edu g.towers@ucl.ac.uk c.jolly@ucl.ac.uk adolfo.garcia-sastre@mssm.edu
Clare Jolly
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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  • For correspondence: nevan.krogan@ucsf.edu g.towers@ucl.ac.uk c.jolly@ucl.ac.uk adolfo.garcia-sastre@mssm.edu
Gregory J. Towers
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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  • For correspondence: nevan.krogan@ucsf.edu g.towers@ucl.ac.uk c.jolly@ucl.ac.uk adolfo.garcia-sastre@mssm.edu
Nevan J. Krogan
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
6Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • ORCID record for Nevan J. Krogan
  • For correspondence: nevan.krogan@ucsf.edu g.towers@ucl.ac.uk c.jolly@ucl.ac.uk adolfo.garcia-sastre@mssm.edu
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Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide and massive societal and economic burden. Recently, a new variant of SARS-CoV-2, known as B.1.1.7, was first detected in the United Kingdom and is spreading in several other countries, heightening public health concern and raising questions as to the resulting effectiveness of vaccines and therapeutic interventions. We and others previously identified host-directed therapies with antiviral efficacy against SARS-CoV-2 infection. Less prone to the development of therapy resistance, host-directed drugs represent promising therapeutic options to combat emerging viral variants as host genes possess a lower propensity to mutate compared to viral genes. Here, in the first study of the full-length B.1.1.7 variant virus, we find two host-directed drugs, plitidepsin (aplidin; inhibits translation elongation factor eEF1A) and ralimetinib (inhibits p38 MAP kinase cascade), as well as remdesivir, to possess similar antiviral activity against both the early-lineage SARS-CoV-2 and the B.1.1.7 variant, evaluated in both human gastrointestinal and lung epithelial cell lines. We find that plitidepsin is over an order of magnitude more potent than remdesivir against both viruses. These results highlight the importance of continued development of host-directed therapeutics to combat current and future coronavirus variant outbreaks.

Competing Interest Statement

The Garcia-Sastre Laboratory has received research support from Pfizer, Senhwa Biosciences and 7Hills Pharma. Adolfo Garcia-Sastre has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Accurius and Esperovax. The Krogan Laboratory receives funding from Roche and VIR and Nevan Krogan has consulting agreements with Maze Therapeutics and Interline Therapeutics. Kevan Shokat has consulting agreements for the following companies involving cash and/or stock compensation: Black Diamond Therapeutics, BridGene Biosciences, Denali Therapeutics, Dice Molecules, eFFECTOR Therapeutics, Erasca, Genentech/Roche, Janssen Pharmaceuticals, Kumquat Biosciences, Kura Oncology, Merck, Mitokinin, Petra Pharma, Revolution Medicines, Type6 Therapeutics, Venthera, Wellspring Biosciences (Araxes Pharma), Turning Point Therapeutics, Ikena, Nextech. Pablo Aviles is an employee and shareholder of PharmaMar, SA (Madrid, Spain).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 24, 2021.
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Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant
Ann-Kathrin Reuschl, Lucy G. Thorne, Lorena Zuliani-Alvarez, Mehdi Bouhaddou, Kirsten Obernier, Margaret Soucheray, Jane Turner, Jacqueline M. Fabius, Gina T. Nguyen, Danielle L. Swaney, Romel Rosales, Kris M. White, Pablo Avilés, Ilsa T. Kirby, James E. Melnyk, Ying Shi, Ziyang Zhang, Kevan M. Shokat, Adolfo García-Sastre, Clare Jolly, Gregory J. Towers, Nevan J. Krogan
bioRxiv 2021.01.24.427991; doi: https://doi.org/10.1101/2021.01.24.427991
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Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant
Ann-Kathrin Reuschl, Lucy G. Thorne, Lorena Zuliani-Alvarez, Mehdi Bouhaddou, Kirsten Obernier, Margaret Soucheray, Jane Turner, Jacqueline M. Fabius, Gina T. Nguyen, Danielle L. Swaney, Romel Rosales, Kris M. White, Pablo Avilés, Ilsa T. Kirby, James E. Melnyk, Ying Shi, Ziyang Zhang, Kevan M. Shokat, Adolfo García-Sastre, Clare Jolly, Gregory J. Towers, Nevan J. Krogan
bioRxiv 2021.01.24.427991; doi: https://doi.org/10.1101/2021.01.24.427991

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