Design, development and enhanced efficacy of host-derived antiviral peptides to prevent herpes simplex virus type 1 infection

Herpes simplex virus (HSV) remains a pervasive global health concern and has the ability to challenge current therapeutic strategies because of its frequent recurrence and drug resistance. This research aimed to disrupt the critical interaction between the viral glycoprotein gD and the host cell receptor of herpes simplex virus, thereby blocking viral infection as a novel antiviral approach. An HVEM-derived native peptide NP (KEACGELTGTVCEP) targeting HSV was rationally designed, with no cytotoxicity and approximately 50% antiviral protection in vitro. Through computational residue scanning, docking and molecular dynamic simulation, seven modified variations of peptides were created to increase the potency and stability, which revealed that the modified peptide F4 with improved binding affinity docking. In vitro tests indicated its dose-dependent antiviral activity, and 60.58% protection at 250 µg/ml was achieved without toxicity. Although relatively less effective than Acyclovir, F4 (RQACGELTGTVCEP) has promising therapeutic potential. This integrated approach highlights the viability of Optimized HVEM-derived peptides as promising candidates with demonstrated antiviral efficacy, offering a strong foundation for future anti-HSV drug development.