title: Host defense peptide-derived privileged scaffolds for anti-infective drug discovery.
abstract: 'Privileged scaffolds' are molecular frameworks which have been successfully exploited for small molecule drug discovery. Peptide privileged scaffolds, featuring a strictly conserved multiple-disulfide framework and high variability in the rest of the sequence, display a broad range of biological effects, including antimicrobial and antiviral activity. Unlike small molecules, however, the cost of manufacturing these peptides is high, and their synthesis challenging. We previously described a simplified privileged scaffold corresponding to the γ-core of human β-defensin-3 (HBD3). The γ-core is a common structural signature found in virtually all host defense peptides (HDPs) stabilized by multiple disulfides, and we showed that for HBD3, it represents the evolutionary starting point of the full-length molecule and, thus, is itself a primordial HDP. Accordingly, we showed that the peptide folded rapidly and was stable in human serum, and displayed many of the biological activities of HBD3. We report here that in addition to the previously reported antibacterial activity on planktonic bacteria, the γ-core peptide is active against biofilm formation and maturation. We also show that it is readily cell penetrant, like HBD3, although with a different mechanism, which is independent from CD98. Overall, the potency of the single-disulfide, 23-amino acid γ-core is comparable with the full-length peptide across the whole spectrum of examined properties, and the peptide is not toxic to human cells. The HBD3 γ-core peptide may therefore represent the first example of an economically viable lead peptide derived from a HDP privileged scaffold. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
authors.affiliation: CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145, Naples, Italy.
authors.forename: Ersilia
authors.initials: E
authors.lastname: Nigro
authors.affiliation: CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145, Naples, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Colavita
authors.affiliation: CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sarnataro
authors.affiliation: CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131, Naples, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Scudiero
authors.affiliation: CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145, Naples, Italy.|Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, Second University of Naples, Via Vivaldi 43, 81100, Caserta, Italy.
authors.forename: Aurora
authors.initials: A
authors.lastname: Daniele
authors.affiliation: CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145, Naples, Italy.|IRCCS-SDN Foundation, Via Emanuele Gianturco 113, 80142, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvatore
authors.affiliation: CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145, Naples, Italy.|PeptiPharma, Viale Città D'Europa 679, 00144, Rome, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Pessi
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D023083:beta-Defensins / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; C422950:DEFB103A protein, human; D010455:Peptides; D023083:beta-Defensins
keywords: antibacterial; antiviral; cysteine-stabilized host defense peptides; human β-defensin 3; innate immunity