Exploring the Potential of HIV Integrase Inhibitors as Therapeutic Agents Against HSV and HCMV: A Molecular Docking Study

Purpose: The worldwide threat of herpes virus infections and their resistance against the existing drugs creates an urgent need for the development of novel drug candidates. An RNase H like domain is present in the protein encoded by the highly conserved ul15 gene (UL15) of Herpes Simplex Virus, ul89 gene encoded protein (UL89) of Human Cytomegalo Virus and Human Immunodeficiency Virus (HIV) integrase proteins. This provided a way repurpose HIV integrase inhibitors as HSV UL15 and HCMV UL89 inhibitors. Materials and Methods: The protein sequences were aligned using the Clustal Omega software to determine the conserved amino acid positions. Schrodinger software was used for docking studies, protein–ligand interaction and simulation studies. The selected drugs were screened to analyse their anti-HSV-1 and HSV-2 activities by Cytopathic effect (CPE) inhibition assay and RT-PCR using Vero cells as host. The experiments were further analyzed by the two-way ANOVA test using Bonferroni’s post-HOC using GraphPad Prism software version 8.0.2. The RT-PCR experimental results were analyzed using the 2^−∆∆Ct Livak method to determine the fold reduction in viral gene expression. Results: The in-silico studies showed the binding abilities of anti-HIV drugs to the active site of UL15 and UL89 by blocking their metal ions, similar to HIV integrase. Among the anti-HIV drugs tested, Elvitegravir and raltegravir were most effective in controlling the HSV-1 and HSV-2 infections at concentrations as low as 1.6 µg/mL when tested with 10TCID₅₀ viral challenge dose. Elvitegravir was most effective in reducing the viral gene expression as tested by RT-PCR. Conclusion: The tested FDA approved drug molecules showed the potential to be repurposed as an antiHSV and antiHCMV agent. The in silico and in vitro results warrant further investigation in preclinical and clinical studies to validate its therapeutic potential and safety for HSV-related infections.