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Binding of SARS-CoV-2 spike protein to ACE2 is disabled by thiol-based drugs; evidence from in vitro SARS-CoV-2 infection studies

Kritika Khanna, Wilfred Raymond, Annabelle R. Charbit, Jing Jin, Irina Gitlin, Monica Tang, Hannah S. Sperber, Sergej Franz, Satish Pillai, Graham Simmons, John V. Fahy
doi: https://doi.org/10.1101/2020.12.08.415505
Kritika Khanna
1Cardiovascular Research Institute, University of California San Francisco, San Francisco, California
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Wilfred Raymond
1Cardiovascular Research Institute, University of California San Francisco, San Francisco, California
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Annabelle R. Charbit
1Cardiovascular Research Institute, University of California San Francisco, San Francisco, California
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Jing Jin
3Vitalant Research Institute, San Francisco, California
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Irina Gitlin
1Cardiovascular Research Institute, University of California San Francisco, San Francisco, California
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Monica Tang
2Division of Pulmonary, Critical Care, Allergy and Sleep and the Department of Medicine, University of California San Francisco, San Francisco, California
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Hannah S. Sperber
3Vitalant Research Institute, San Francisco, California
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Sergej Franz
3Vitalant Research Institute, San Francisco, California
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Satish Pillai
3Vitalant Research Institute, San Francisco, California
4Department of Laboratory Medicine, University of California San Francisco, San Francisco, California
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Graham Simmons
3Vitalant Research Institute, San Francisco, California
4Department of Laboratory Medicine, University of California San Francisco, San Francisco, California
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John V. Fahy
1Cardiovascular Research Institute, University of California San Francisco, San Francisco, California
2Division of Pulmonary, Critical Care, Allergy and Sleep and the Department of Medicine, University of California San Francisco, San Francisco, California
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  • For correspondence: john.fahy@ucsf.edu
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Abstract

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the SARS-CoV-2 spike protein is an envelope glycoprotein that binds angiotensin converting enzyme 2 as an entry receptor. The capacity of enveloped viruses to infect host cells depends on a precise thiol/disulfide balance in their surface glycoprotein complexes. To determine if cystines in the SARS-CoV-2 spike protein maintain a native binding interface that can be disrupted by drugs that cleave cystines, we tested if thiol-based drugs have efficacy in receptor binding and cell infection assays. We found that thiol-based drugs, cysteamine and WR-1065 (the active metabolite of amifostine) in particular, decrease binding of SARS-CoV-2 spike protein to its receptor, decrease the entry efficiency of SARS-CoV-2 spike pseudotyped virus, and inhibit SARS-CoV-2 live virus infection. Our findings uncover a vulnerability of SARS-CoV-2 to thiol-based drugs and provide rationale to test thiol-based drugs, especially cysteamine and amifostine, as novel treatments for COVID-19.

One Sentence Summary Thiol-based drugs decrease binding of SARS-CoV-2 spike protein to its receptor and inhibit SARS-CoV-2 cell entry.

Competing Interest Statement

John Fahy, Irina Gitlin and Wilfred Raymond are inventors on patent applications related to use of thiol-based drugs as treatments for mucus pathology and COVID19. The other authors have no 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. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 08, 2020.
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Binding of SARS-CoV-2 spike protein to ACE2 is disabled by thiol-based drugs; evidence from in vitro SARS-CoV-2 infection studies
Kritika Khanna, Wilfred Raymond, Annabelle R. Charbit, Jing Jin, Irina Gitlin, Monica Tang, Hannah S. Sperber, Sergej Franz, Satish Pillai, Graham Simmons, John V. Fahy
bioRxiv 2020.12.08.415505; doi: https://doi.org/10.1101/2020.12.08.415505
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Binding of SARS-CoV-2 spike protein to ACE2 is disabled by thiol-based drugs; evidence from in vitro SARS-CoV-2 infection studies
Kritika Khanna, Wilfred Raymond, Annabelle R. Charbit, Jing Jin, Irina Gitlin, Monica Tang, Hannah S. Sperber, Sergej Franz, Satish Pillai, Graham Simmons, John V. Fahy
bioRxiv 2020.12.08.415505; doi: https://doi.org/10.1101/2020.12.08.415505

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