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Herpes simplex virus (HSV) infections have become a public health problem worldwide. The emergence of acyclovir-resistant viral strains and the failure of vaccination to prevent herpetic infections have prompted the search for new antiviral drugs. Accordingly, the present study was undertaken to synthesize chemically and evaluate Dermaseptin S4 (S4), an anti-microbial peptide derived from amphibian skin, and its derivatives in terms of anti-herpetic activity. The effects of biochemical modifications on their antimicrobial potential were also investigated. The peptides were incubated together with HSV-2 on target cells under various conditions, and the antiviral effects were examined via a cell metabolic labeling method. The findings revealed that DS4 derivatives elicited concentration-dependent antiviral activity at micromole concentrations. The biochemical modifications of S4 allowed for the reduction of peptide cytotoxicity without altering antiviral activity. Dermaseptins were added at different times during the viral cycle to investigate the mode of antiviral action. At the highest non-cytotoxic concentrations, most of the tested derivatives were noted to exhibit high antiviral activity particularly when pre-incubated with free herpes viruses prior to infection. Among these peptides, K4K20S4 exhibited the highest antiviral activity against HSV-2 sensitive and resistant strains. Interestingly, the antiviral activity of K4K20S4 was effective on both acyclovir-resistant and -sensitive viruses. The findings indicate that K4K20S4 can be considered a promising candidate for future application as a therapeutic virucidal agent for the treatment of herpes viruses. J. Med. Virol. 85:272-281, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]