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Inhibition of exchange proteins directly activated by cAMP as a strategy for broad-spectrum antiviral development.

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Title: Inhibition of exchange proteins directly activated by cAMP as a strategy for broad-spectrum antiviral development.
Authors: Boulton, Stephen1,2 sboulton@ohri.ca, Crupi, Mathieu J. F.1,2, Singh, Siddharth1,2, Carter-Timofte, Madalina E.3, Azad, Taha1,2,4,5, Organ, Bailey C.1,2, Xiaohong He1,2, Gill, Rida1,2, Neault, Serge1,2, Jamieson, Taylor1,2, Dave, Jaahnavi1,2, Kurmasheva, Naziia3, Austin, Bradley1, Petryk, Julia1, Singaravelu, Ragunath1,2,6, Ben Zhen Huang1,2, Franco, Noah1,2, Babu, Kaaviya1,2, Parks, Robin J.1,2,7, Ilkow, Carolina S.1,2
Source: Journal of Biological Chemistry. Jun2023, Vol. 299 Issue 6, p1-17. 17p.
Subjects: Monkeypox, Viral mutation, Cytoskeleton, Antiviral agents, Measles virus, Plant viruses
Abstract: The recent SARS-CoV-2 and mpox outbreaks have highlighted the need to expand our arsenal of broad-spectrum antiviral agents for future pandemic preparedness. Hostdirected antivirals are an important tool to accomplish this as they typically offer protection against a broader range of viruses than direct-acting antivirals and have a lower susceptibility to viral mutations that cause drug resistance. In this study, we investigate the exchange protein activated by cAMP (EPAC) as a target for broad-spectrum antiviral therapy. We find that the EPAC-selective inhibitor, ESI-09, provides robust protection against a variety of viruses, including SARS-CoV-2 and Vaccinia (VACV)--an orthopox virus from the same family as mpox. We show, using a series of immunofluorescence experiments, that ESI-09 remodels the actin cytoskeleton through Rac1/Cdc42 GTPases and the Arp2/3 complex, impairing internalization of viruses that use clathrin-mediated endocytosis (e.g. VSV) or micropinocytosis (e.g. VACV). Additionally, we find that ESI-09 disrupts syncytia formation and inhibits cell-to-cell transmission of viruses such as measles and VACV. When administered to immune-deficient mice in an intranasal challenge model, ESI-09 protects mice from lethal doses of VACV and prevents formation of pox lesions. Altogether, our finding shows that EPAC antagonists such as ESI-09 are promising candidates for broad-spectrum antiviral therapy that can aid in the fight against ongoing and future viral outbreaks. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. 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.)
Database: Engineering Source
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PubType: Academic Journal
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  Data: Inhibition of exchange proteins directly activated by cAMP as a strategy for broad-spectrum antiviral development.
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  Data: <searchLink fieldCode="AR" term="%22Boulton%2C+Stephen%22">Boulton, Stephen</searchLink><relatesTo>1,2</relatesTo><i> sboulton@ohri.ca</i><br /><searchLink fieldCode="AR" term="%22Crupi%2C+Mathieu+J%2E+F%2E%22">Crupi, Mathieu J. F.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Singh%2C+Siddharth%22">Singh, Siddharth</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Carter-Timofte%2C+Madalina+E%2E%22">Carter-Timofte, Madalina E.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Azad%2C+Taha%22">Azad, Taha</searchLink><relatesTo>1,2,4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Organ%2C+Bailey+C%2E%22">Organ, Bailey C.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Xiaohong+He%22">Xiaohong He</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Gill%2C+Rida%22">Gill, Rida</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Neault%2C+Serge%22">Neault, Serge</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Jamieson%2C+Taylor%22">Jamieson, Taylor</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Dave%2C+Jaahnavi%22">Dave, Jaahnavi</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Kurmasheva%2C+Naziia%22">Kurmasheva, Naziia</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Austin%2C+Bradley%22">Austin, Bradley</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Petryk%2C+Julia%22">Petryk, Julia</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Singaravelu%2C+Ragunath%22">Singaravelu, Ragunath</searchLink><relatesTo>1,2,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Ben+Zhen+Huang%22">Ben Zhen Huang</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Franco%2C+Noah%22">Franco, Noah</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Babu%2C+Kaaviya%22">Babu, Kaaviya</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Parks%2C+Robin+J%2E%22">Parks, Robin J.</searchLink><relatesTo>1,2,7</relatesTo><br /><searchLink fieldCode="AR" term="%22Ilkow%2C+Carolina+S%2E%22">Ilkow, Carolina S.</searchLink><relatesTo>1,2</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. Jun2023, Vol. 299 Issue 6, p1-17. 17p.
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  Data: <searchLink fieldCode="DE" term="%22Monkeypox%22">Monkeypox</searchLink><br /><searchLink fieldCode="DE" term="%22Viral+mutation%22">Viral mutation</searchLink><br /><searchLink fieldCode="DE" term="%22Cytoskeleton%22">Cytoskeleton</searchLink><br /><searchLink fieldCode="DE" term="%22Antiviral+agents%22">Antiviral agents</searchLink><br /><searchLink fieldCode="DE" term="%22Measles+virus%22">Measles virus</searchLink><br /><searchLink fieldCode="DE" term="%22Plant+viruses%22">Plant viruses</searchLink>
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  Data: The recent SARS-CoV-2 and mpox outbreaks have highlighted the need to expand our arsenal of broad-spectrum antiviral agents for future pandemic preparedness. Hostdirected antivirals are an important tool to accomplish this as they typically offer protection against a broader range of viruses than direct-acting antivirals and have a lower susceptibility to viral mutations that cause drug resistance. In this study, we investigate the exchange protein activated by cAMP (EPAC) as a target for broad-spectrum antiviral therapy. We find that the EPAC-selective inhibitor, ESI-09, provides robust protection against a variety of viruses, including SARS-CoV-2 and Vaccinia (VACV)--an orthopox virus from the same family as mpox. We show, using a series of immunofluorescence experiments, that ESI-09 remodels the actin cytoskeleton through Rac1/Cdc42 GTPases and the Arp2/3 complex, impairing internalization of viruses that use clathrin-mediated endocytosis (e.g. VSV) or micropinocytosis (e.g. VACV). Additionally, we find that ESI-09 disrupts syncytia formation and inhibits cell-to-cell transmission of viruses such as measles and VACV. When administered to immune-deficient mice in an intranasal challenge model, ESI-09 protects mice from lethal doses of VACV and prevents formation of pox lesions. Altogether, our finding shows that EPAC antagonists such as ESI-09 are promising candidates for broad-spectrum antiviral therapy that can aid in the fight against ongoing and future viral outbreaks. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. 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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      – Type: doi
        Value: 10.1016/j.jbc.2023.104749
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      – Code: eng
        Text: English
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        PageCount: 17
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      – SubjectFull: Monkeypox
        Type: general
      – SubjectFull: Viral mutation
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      – SubjectFull: Cytoskeleton
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      – SubjectFull: Antiviral agents
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      – SubjectFull: Plant viruses
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