Rossella Tarallo,1 Tom P Carberry,2 Annarita Falanga,1 Mariateresa Vitiello,3 Stefania Galdiero,1 Massimiliano Galdiero,3 Marcus Weck21Dipartimento di Farmacia, Università di Napoli "Federico II," and DFM Scarl, Napoli, Italia; 2Molecular Design Institute and Department of Chemistry, New York University, New York, NY, USA; 3Dipartimento di Medicina Sperimentale, Seconda Università degli Studi di Napoli, Napoli, ItaliaAbstract: This contribution reports the synthesis of a poly(amide)-based dendrimer functionalized at the termini with a membrane-interacting peptide derived from the herpes simplex virus (HSV) type 1 glycoprotein H, namely gH625-644. This peptide has been shown to interact with model membranes and to inhibit viral infectivity. The peptidodendrimer inhibits both HSV-1 and HSV-2 at a very early stage of the entry process, most likely through an interaction with the viral envelope glycoproteins; thus, preventing the virus from coming into close contact with cellular membranes, a prerequisite of viral internalization. The 50% inhibitory concentration was 100 and 300 nM against HSV-1 and HSV-2 respectively, with no evidence of cell toxicity at these concentrations. These results show that the functionalization of a dendrimer with the peptide sequence derived from an HSV glycoprotein shows promising inhibitory activity towards viruses of the Herpesviridae family.Keywords: peptidodendrimer, antiviral activity, membranotropic peptides