The human α-defensin-derived peptide HD5(1–9) inhibits cellular attachment and entry of human cytomegalovirus

Human cytomegalovirus (HCMV) infection causes severe illness in newborns and immunocompromised patients. Since treatment options are limited there is an unmet need for new therapeutic approaches. Defensins are cationic peptides, produced by various human tissues, which serve as antimicrobial effectors of the immune system. Furthermore, some defensins are proteolytically cleaved, resulting in the generation of smaller fragments with increased activity. Together, this led us to hypothesize that defensin-derived peptides are natural human inhibitors of virus infection with low toxicity. We screened several human defensin HNP4- and HD5-derived peptides and found HD5(1–9) to be antiviral without toxicity at high concentrations. HD5(1–9) inhibited HCMV cellular attachment and thereby entry and was active against primary as well as a multiresistant HCMV isolate. Moreover, cysteine and arginine residues were identified to mediate the antiviral activity of HD5(1–9). Altogether, defensin-derived peptides, in particular HD5(1–9), qualify as promising candidates for further development as a novel class of HCMV entry inhibitors. •Short α-defensin HD5-derived peptide HD5(1–9) inhibits infection with human cytomegalovirus.•HD5(1–9) inhibits lab-adapted as well as primary and multiresistant HCMV strains.•HD5(1–9) is non-toxic to cells and does not impede embryonic development in concentrations used to inhibit infection.•Mode-of-action of HD5(1–9) is to inhibit attachment of HCMV particles to cells.