079 | Pharmacological modulation of the STING pathway as an antiviral strategy against HSV-1

Federica Mastrolembo Barnà^1|2, Paola Trischitta^1|2, Marianna Costa^1|2, Antonella Torre³, Alessia Onali³, Angela Pagliaro³, Alberto Deplano³, Elias Maccioni³, Rita Meleddu³, Simona Distinto³, Rosamaria Pennisi¹, Maria Teresa Sciortino¹ | ¹Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Italy; ²Dep of chemistry, biology and biotechnology, University of Perugia, Italy; ³Department of Life and Environmental Sciences, Section of Drug Sciences, University of Cagliari, University Campus, Monserrato [CA], Italy.

Herpes Simplex Virus type 1 (HSV-1) is a highly prevalent human pathogen capable of evading the host innate immune response by inhibiting interferon signaling, thereby promoting the establishment of persistent and recurrent infections. A key component of the innate antiviral immune response is the cGAS–STING (Stimulator of Interferon Genes) signaling pathway, which is involved in the recognition of viral DNA in the cytosol. Upon detection of viral DNA by cGAS, STING is activated and induces the production of type I interferons (IFN-I) and pro-inflammatory cytokines essential for controllingviral replication [1]. HSV-1 directly interferes with the STING pathway, impairing the interferon response and weakening host defenses. Consequently, pharmacological activation of STING represents an innovative and promising strategy to restore innate immunity and counteract viral immune evasion mechanisms [2]. This study aims to identify novel STING agonists contributing to the development of innovative therapeutic strategies. The EMACA compound library was developed using a rational design approach that integrated medicinal chemistry strategies and computer-aided drug design (CADD) techniques. Selected compounds were synthesized, characterized, and subjected to experimental validation.Their antiviral efficacy was assessed by plaque assay in Vero cells and by Western blot analysis of STING phosphorylation levels. The results indicate that four of the tested compounds reduce the release of viral particles, suggesting a potential antiviral activity mediated by activation of the STING pathway. Overall, these data highlight the potential of EMACA compounds as STING pathway agonists with antiviral activity against HSV-1 and support the hypothesis that modulation of innate immunity may represent an innovative therapeutic strategy worthy of further investigation.