Peniterphenyl A is a natural product obtained from a deep-sea-derived Penicillium sp. Peniterphenyl A inhibits HSV-1/2 virus entry into cells and may block HSV-1/2 infection through direct interaction with virus envelope glycoprotein D to interfere with virus adsorption and membrane fusion. Peniterphenyl A is a promising lead compound against HSV-1/2.