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Thiol-based chemical probes exhibit antiviral activity against SARS-CoV-2 via allosteric disulfide disruption in the spike glycoprotein.

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Title: Thiol-based chemical probes exhibit antiviral activity against SARS-CoV-2 via allosteric disulfide disruption in the spike glycoprotein.
Authors: Yunlong Shi1, Zeida, Ari2, Edwards, Caitlin E.3, Mallory, Michael L.3, Sastre, Santiago2, Machado, Matías R.4, Pickles, Raymond J.5,6, Ling Fu7, Keke Liu7, Jing Yang7, Baric, Ralph S.3, Boucher, Richard C.5 richard_boucher@med.unc.edu, Radi, Rafael2 rradi@fmed.edu.uy, Carroll, Kate S.1 kcarroll@scripps.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 2/8/2022, Vol. 119 Issue 6, p1-9. 9p.
Subjects: SARS-CoV-2, Angiotensin converting enzyme, Reducing agents, COVID-19 pandemic, Fireproofing agents, Coronaviruses
Abstract: The development of small-molecules targeting different components of SARS-CoV-2 is a key strategy to complement antibody-based treatments and vaccination campaigns in managing the COVID-19 pandemic. Here, we show that two thiol-based chemical probes that act as reducing agents, P2119 and P2165, inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, the angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine pro-filing link the antiviral activity to the reduction of key disulfides, specifically by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif in the receptor binding domain (RBD) of the spike glycoprotein. Computational analyses provide insight into conformation changes that occur when these disulfides break or form, consistent with an allosteric role, and indicate that P2119/P2165 target a conserved hydrophobic binding pocket in the RBD with the benzyl thiol-reducing moiety pointed directly toward Cys432. These collective findings establish the vulnerability of human coronaviruses to thiol-based chemical probes and lay the groundwork for developing compounds of this class, as a strategy to inhibit the SARS-CoV-2 infection by shifting the spike glycoprotein redox scaffold. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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DbLabel: Engineering Source
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  Data: Thiol-based chemical probes exhibit antiviral activity against SARS-CoV-2 via allosteric disulfide disruption in the spike glycoprotein.
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  Data: <searchLink fieldCode="AR" term="%22Yunlong+Shi%22">Yunlong Shi</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Zeida%2C+Ari%22">Zeida, Ari</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Edwards%2C+Caitlin+E%2E%22">Edwards, Caitlin E.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Mallory%2C+Michael+L%2E%22">Mallory, Michael L.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Sastre%2C+Santiago%22">Sastre, Santiago</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Machado%2C+Matías+R%2E%22">Machado, Matías R.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Pickles%2C+Raymond+J%2E%22">Pickles, Raymond J.</searchLink><relatesTo>5,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Ling+Fu%22">Ling Fu</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Keke+Liu%22">Keke Liu</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Jing+Yang%22">Jing Yang</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Baric%2C+Ralph+S%2E%22">Baric, Ralph S.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Boucher%2C+Richard+C%2E%22">Boucher, Richard C.</searchLink><relatesTo>5</relatesTo><i> richard_boucher@med.unc.edu</i><br /><searchLink fieldCode="AR" term="%22Radi%2C+Rafael%22">Radi, Rafael</searchLink><relatesTo>2</relatesTo><i> rradi@fmed.edu.uy</i><br /><searchLink fieldCode="AR" term="%22Carroll%2C+Kate+S%2E%22">Carroll, Kate S.</searchLink><relatesTo>1</relatesTo><i> kcarroll@scripps.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 2/8/2022, Vol. 119 Issue 6, p1-9. 9p.
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  Data: <searchLink fieldCode="DE" term="%22SARS-CoV-2%22">SARS-CoV-2</searchLink><br /><searchLink fieldCode="DE" term="%22Angiotensin+converting+enzyme%22">Angiotensin converting enzyme</searchLink><br /><searchLink fieldCode="DE" term="%22Reducing+agents%22">Reducing agents</searchLink><br /><searchLink fieldCode="DE" term="%22COVID-19+pandemic%22">COVID-19 pandemic</searchLink><br /><searchLink fieldCode="DE" term="%22Fireproofing+agents%22">Fireproofing agents</searchLink><br /><searchLink fieldCode="DE" term="%22Coronaviruses%22">Coronaviruses</searchLink>
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  Label: Abstract
  Group: Ab
  Data: The development of small-molecules targeting different components of SARS-CoV-2 is a key strategy to complement antibody-based treatments and vaccination campaigns in managing the COVID-19 pandemic. Here, we show that two thiol-based chemical probes that act as reducing agents, P2119 and P2165, inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, the angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine pro-filing link the antiviral activity to the reduction of key disulfides, specifically by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif in the receptor binding domain (RBD) of the spike glycoprotein. Computational analyses provide insight into conformation changes that occur when these disulfides break or form, consistent with an allosteric role, and indicate that P2119/P2165 target a conserved hydrophobic binding pocket in the RBD with the benzyl thiol-reducing moiety pointed directly toward Cys432. These collective findings establish the vulnerability of human coronaviruses to thiol-based chemical probes and lay the groundwork for developing compounds of this class, as a strategy to inhibit the SARS-CoV-2 infection by shifting the spike glycoprotein redox scaffold. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2120419119
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        Text: English
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        Type: general
      – SubjectFull: Angiotensin converting enzyme
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      – SubjectFull: Reducing agents
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      – SubjectFull: Fireproofing agents
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