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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]
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Database: Engineering Source
Description
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]
ISSN:00219258
DOI:10.1016/j.jbc.2023.104749