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The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters

Lisa Miorin, Chad E. Mire, Shahin Ranjbar, Adam J. Hume, Jessie Huang, View ORCID ProfileNicholas A. Crossland, Kris M White, Manon Laporte, Thomas Kehrer, Viraga Haridas, Elena Moreno, Aya Nambu, Sonia Jangra, Anastasija Cupic, View ORCID ProfileMarion Dejosez, Kristine A. Abo, Anna E. Tseng, Rhiannon B. Werder, Raveen Rathnasinghe, Tinaye Mutetwa, Irene Ramos, Julio Sainz de Aja, Carolina Garcia de Alba Rivas, Michael Schotsaert, Ronald B. Corley, James V. Falvo, Ana Fernandez-Sesma, Carla Kim, Jean-François Rossignol, Andrew A. Wilson, Thomas Zwaka, Darrell N. Kotton, Elke Mühlberger, Adolfo García-Sastre, Anne E. Goldfeld
doi: https://doi.org/10.1101/2022.02.08.479634
Lisa Miorin
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • For correspondence: lisa.miorin@mssm.edu anne.goldfeld@childrens.harvard.edu
Chad E. Mire
3University of Texas Medical Branch, Galveston, TX, USA
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Shahin Ranjbar
4Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
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Adam J. Hume
5National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
6Department of Microbiology, Boston University School of Medicine, Boston, MA, USA
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Jessie Huang
7Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
8The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, USA
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Nicholas A. Crossland
5National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
9Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
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  • ORCID record for Nicholas A. Crossland
Kris M White
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Manon Laporte
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Thomas Kehrer
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Viraga Haridas
4Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
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Elena Moreno
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Aya Nambu
4Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
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Sonia Jangra
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Anastasija Cupic
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Marion Dejosez
10Cell, Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai; New York, NY, USA
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  • ORCID record for Marion Dejosez
Kristine A. Abo
7Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
8The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, USA
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Anna E. Tseng
5National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
9Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
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Rhiannon B. Werder
7Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
8The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, USA
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Raveen Rathnasinghe
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Tinaye Mutetwa
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Irene Ramos
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Julio Sainz de Aja
11Stem Cell Program, Boston Children’s Hospital, Boston, MA, USA
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Carolina Garcia de Alba Rivas
11Stem Cell Program, Boston Children’s Hospital, Boston, MA, USA
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Michael Schotsaert
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Ronald B. Corley
5National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
9Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
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James V. Falvo
4Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
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Ana Fernandez-Sesma
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Carla Kim
11Stem Cell Program, Boston Children’s Hospital, Boston, MA, USA
12Harvard Stem Cell Institute, Cambridge, Massachusetts
13Department of Genetics, Harvard Medical School, Boston, MA, USA
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Jean-François Rossignol
14Romark Institute for Medical Research, Tampa, FL, USA
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Andrew A. Wilson
7Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
8The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, USA
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Thomas Zwaka
10Cell, Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai; New York, NY, USA
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Darrell N. Kotton
7Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
8The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, USA
9Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
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Elke Mühlberger
5National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
6Department of Microbiology, Boston University School of Medicine, Boston, MA, USA
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Adolfo García-Sastre
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
15Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
16Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
17Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Anne E. Goldfeld
4Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
18Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
19Department of Immunology and Infectious Diseases, Harvard T.C. Chan School of Public Health, Boston, MA, USA
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  • For correspondence: lisa.miorin@mssm.edu anne.goldfeld@childrens.harvard.edu
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Abstract

A well-tolerated and cost-effective oral drug that blocks SARS-CoV-2 growth and dissemination would be a major advance in the global effort to reduce COVID-19 morbidity and mortality. Here, we show that the oral FDA-approved drug nitazoxanide (NTZ) significantly inhibits SARS-CoV-2 viral replication and infection in different primate and human cell models including stem cell-derived human alveolar epithelial type 2 cells. Furthermore, NTZ synergizes with remdesivir, and it broadly inhibits growth of SARS-CoV-2 variants B.1.351 (beta), P.1 (gamma), and B.1617.2 (delta) and viral syncytia formation driven by their spike proteins. Strikingly, oral NTZ treatment of Syrian hamsters significantly inhibits SARS-CoV-2-driven weight loss, inflammation, and viral dissemination and syncytia formation in the lungs. These studies show that NTZ is a novel host-directed therapeutic that broadly inhibits SARS-CoV-2 dissemination and pathogenesis in human and hamster physiological models, which supports further testing and optimization of NTZ-based therapy for SARS-CoV-2 infection alone and in combination with antiviral drugs.

Competing Interest Statement

The AG-S laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, and Merck outside of the reported work. AG-S has consulting agreements for the following companies involving cash and/or stock outside of the reported work: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, Paratus, CureLab Oncology, CureLab Veterinary, and Pfizer. AG-S is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. J-FR is an employee of, and owns an equity interest in, Romark, L.C. The authors claim no other competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters
Lisa Miorin, Chad E. Mire, Shahin Ranjbar, Adam J. Hume, Jessie Huang, Nicholas A. Crossland, Kris M White, Manon Laporte, Thomas Kehrer, Viraga Haridas, Elena Moreno, Aya Nambu, Sonia Jangra, Anastasija Cupic, Marion Dejosez, Kristine A. Abo, Anna E. Tseng, Rhiannon B. Werder, Raveen Rathnasinghe, Tinaye Mutetwa, Irene Ramos, Julio Sainz de Aja, Carolina Garcia de Alba Rivas, Michael Schotsaert, Ronald B. Corley, James V. Falvo, Ana Fernandez-Sesma, Carla Kim, Jean-François Rossignol, Andrew A. Wilson, Thomas Zwaka, Darrell N. Kotton, Elke Mühlberger, Adolfo García-Sastre, Anne E. Goldfeld
bioRxiv 2022.02.08.479634; doi: https://doi.org/10.1101/2022.02.08.479634
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The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters
Lisa Miorin, Chad E. Mire, Shahin Ranjbar, Adam J. Hume, Jessie Huang, Nicholas A. Crossland, Kris M White, Manon Laporte, Thomas Kehrer, Viraga Haridas, Elena Moreno, Aya Nambu, Sonia Jangra, Anastasija Cupic, Marion Dejosez, Kristine A. Abo, Anna E. Tseng, Rhiannon B. Werder, Raveen Rathnasinghe, Tinaye Mutetwa, Irene Ramos, Julio Sainz de Aja, Carolina Garcia de Alba Rivas, Michael Schotsaert, Ronald B. Corley, James V. Falvo, Ana Fernandez-Sesma, Carla Kim, Jean-François Rossignol, Andrew A. Wilson, Thomas Zwaka, Darrell N. Kotton, Elke Mühlberger, Adolfo García-Sastre, Anne E. Goldfeld
bioRxiv 2022.02.08.479634; doi: https://doi.org/10.1101/2022.02.08.479634

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