Proprietary Cationic Lipo-Oligopeptides Inhibit Herpes Simplex Virus-1 Infection

The use of antimicrobial peptides (AMPs) to combat herpes simplex virus type 1 (HSV-1) infection has surged amidst the rise of HSV-1 drug-resistant strains. AMPs offer an unconventional approach to combat HSV-1 infection by exerting their activity on multiple phases of the viral life cycle, while exhibiting low rates of resistance emergence. In this study, an integrated in silico and in vitro approach was used to evaluate six proprietary cationic lipo-oligopeptides (CLOPs) (P226, P359, P577, P581, OB1105, and OB1111) as potential anti-HSV-1 agents. Computational tools were used to predict various physiochemical and pharmacokinetic parameters of CLOPs and to assess their molecular docking and binding affinities for HSV-1 glycoproteins. Our findings showed that CLOPs conform to the Pfizer’s rule, predicting a low risk of toxicity. All CLOPs were predicted to exhibit antiviral activity against HSV-1 and interact with major HSV-1 glycoproteins, with energies ranging from −7.5 to −3.2 Kcal/mol. Next, in vitro cytotoxicity along with viral plaque reduction and attachment assays were performed in eukaryotic cells. Our results confirmed that CLOPs were non-cytotoxic and inhibited HSV-1 plaque formation and viral titers in eukaryotic cells. Notably, the plaques were visually smaller in treated cells than those in the HSV-1 control, suggesting a treatment effect on plaque morphology. Among the tested CLOPs, OB1111 emerged as the best anti-HSV-1 candidate, consistently demonstrating strong antiviral activity across both computational and experimental platforms. OB1111 also exerted a significant antiviral effect at the earliest stage of infection in cells. Collectively, these findings identify OB1111 as a strong candidate for further evaluations of its antiviral effects and mechanisms against HSV-1.