title: Conformational analysis and cytotoxic activities of the frog skin host-defense peptide, hymenochirin-1Pa.
abstract: Hymenochirin-1Pa (LKLSPKTKDTLKKVLKGAIKGAIAIASMA-NH2) is a host-defense peptide first isolated from skin secretions of the frog Pseudhymenochirus merlini (Pipidae). A nuclear magnetic resonance structural investigation demonstrates that the peptide has a random coil conformation in water but, in the membrane-mimetic solvent 50% (v/v) trifluoroethanol-water adopts a well-defined conformation characterized by two α-helical domains from residues K6 to G17 and from G21 to M28, with the N-terminal region unfolded. The presence of a GXXXG domain, the most common structural motif found at the interface between interacting trans-membrane helices, between residues 17 and 21, introduces a kink corresponding to a deviation from linearity of 93 ± 31°. Hymenochirin-1Pa shows broad spectrum anti-bacterial activity, including high potency against multidrug-resistant clinical isolates of Staphylococcus aureus, Acinetobacter baumannii, and Stenotrophomonas maltophilia. The peptide also shows high cytotoxic potency against human non-small lung adenocarcinoma A549 cells, breast adenocarcinoma MDA-MB-231 cells, and colorectal adenocarcinoma HT-29 cells but its therapeutic potential as an anti-cancer agent is limited by moderate hemolytic activity against human erythrocytes and lack of selectivity for tumor cells. Increasing cationicity of the peptide by substituting the Asp(9) residue by either L-Lys (K) or D-Lys (k) has relatively minor effects on antimicrobial and anti-tumor potencies but the [D9k] analog is non-hemolytic LC50 > 400 μM. Thus, [D9k]hymenochirin-1Pa may serve as a template for the design of non-toxic antimicrobial agents for use against multidrug-resistant pathogenic bacteria.
authors.affiliation: Department of Chemical and Geological Sciences, University of Cagliari, Monserrato (CA), Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Serra
authors.affiliation: Department of Biomedical Sciences, Biochemistry Unit, University of Cagliari, Monserrato (CA), Italy. Electronic address: scorciapino@unica.it.
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Scorciapino
authors.affiliation: Department of Biomedical Sciences, Biochemistry Unit, University of Cagliari, Monserrato (CA), Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Manzo
authors.affiliation: Department of Chemical and Geological Sciences, University of Cagliari, Monserrato (CA), Italy.
authors.forename: Mariano
authors.initials: M
authors.lastname: Casu
authors.affiliation: Department of Biomedical Sciences, Biochemistry Unit, University of Cagliari, Monserrato (CA), Italy.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Rinaldi
authors.affiliation: Department of Pharmacology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Samir
authors.initials: S
authors.lastname: Attoub
authors.affiliation: Department of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, United Kingdom.
authors.forename: Milena
authors.initials: M
authors.lastname: Mechkarska
authors.affiliation: Department of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, United Kingdom.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Conlon
mesh_terms: D029845:Amphibian Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000254:growth & development*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D010884:Pipidae; D017433:Protein Structure, Secondary; D012867:Skin / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D029845:Amphibian Proteins; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D003603:Cytotoxins
keywords: 3D structure; Anticancer activity; Antimicrobial peptide; NMR