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

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.

 

Comments:

The study you've described highlights an exciting potential avenue for broad-spectrum antiviral therapy using host-directed antivirals targeting the exchange protein activated by cAMP (EPAC). This approach appears to be promising in protecting against a variety of viruses, including SARS-CoV-2, Vaccinia (VACV), and other viruses.

Here's a breakdown of the key findings and implications of this research:

1. **EPAC as a Target**: The study suggests that EPAC can serve as a target for broad-spectrum antiviral therapy. Targeting host factors like EPAC can be advantageous because they offer protection against a wider range of viruses compared to direct-acting antivirals that target specific viral proteins. Moreover, host-directed antivirals tend to be less susceptible to viral mutations that lead to drug resistance.

2. **EPAC Inhibitor ESI-09**: The EPAC-selective inhibitor ESI-09 is identified as a potent antiviral agent. This inhibitor appears to provide robust protection against various viruses, including SARS-CoV-2 and Vaccinia (VACV), which is noteworthy given the recent outbreaks.

3. **Mechanism of Action**: The study delves into the mechanism by which ESI-09 exerts its antiviral effects. It is shown to remodel the actin cytoskeleton through the involvement of Rac1/Cdc42 GTPases and the Arp2/3 complex. This remodeling interferes with the internalization of viruses that use different entry mechanisms, such as clathrin-mediated endocytosis and micropinocytosis.

4. **Effects on Syncytia Formation and Cell-to-Cell Transmission**: ESI-09 is found to disrupt syncytia formation, which is relevant for viruses like measles. It also inhibits cell-to-cell transmission of viruses, which can be a critical aspect of viral spread.

5. **Animal Model**: The study extends its findings to an animal model. When administered to immune-deficient mice in an intranasal challenge model, ESI-09 protects the mice from lethal doses of VACV and prevents the formation of pox lesions. This suggests potential in vivo efficacy.

6. **Broad-Spectrum Potential**: Overall, the results suggest that EPAC antagonists like ESI-09 have the potential to serve as broad-spectrum antiviral therapies. This is particularly important in the context of pandemic preparedness, where having effective treatments that can combat a variety of viruses is crucial.

It's worth noting that further research, including clinical trials and safety assessments, would be needed to validate the potential of ESI-09 as a broad-spectrum antiviral therapy for use in humans. Additionally, the study's findings may have implications for the development of antiviral strategies beyond the specific viruses mentioned in the study.

Related Products

Cat.No.	Product Name	Information
S7499	ESI-09	ESI-09 is a specific exchange protein directly activated by cAMP (EPAC) inhibitor with IC50 of 3.2 μM and 1.4 μM for EPAC1 and EPAC2, respectively, >100-fold selectivity over PKA.

Related Targets

cAMP