Inhibition of exchange proteins directly activated by cAMP as a strategy for broad-spectrum antiviral development.
J Biol Chem
; 299(6): 104749, 2023 06.
Article
in English
| MEDLINE | ID: covidwho-2292505
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. Host-directed 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.
Keywords
COVID-19; EPAC; ESI-09; HSV-1; Rho GTPases; SARS-CoV-2; VSV; actin; adenovirus; antiviral; measles; mpox; vaccinia
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Vaccinia
/
Mpox (monkeypox)
/
COVID-19
Type of study:
Prognostic study
Topics:
Vaccines
Limits:
Animals
Language:
English
Journal:
J Biol Chem
Year:
2023
Document Type:
Article
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