title: Marked increase in membranolytic selectivity of novel cyclic tachyplesins constrained with an antiparallel two-beta strand cystine knot framework.
abstract: We have developed a highly constrained 18-residue cyclic peptide template based on the antimicrobial peptide tachyplesin-1 that features an end-to-end peptide backbone and a cystine knot-like motif with three evenly spaced disulfide bonds to cross-brace the antiparallel beta-strands and to approximate an amphiphatic "beta-tile"-like structure. Six beta-tile analogs were prepared to correlate different topological patterns with membranolytic specificity. Their conformations and antimicrobial and hemolytic activities were compared with tachyplesin-1 and the recently discovered Rhesus monkey theta defensin (RTD) which contains similar beta-tile structural elements. The beta-tile peptides and RTD retained broad spectrum antimicrobial activities. In general, they were less active than tachyplesin-1 in 10 tested organisms but their activity increased under high-salt (100 mM NaCl) rather than in low-salt conditions. The beta-tile peptides are highly nontoxic to human erythrocytes with EC(25) ranging from 600 to 4000 microM. Collectively, our results show that the design of a highly rigid peptide template is useful for further analog study to dissociate antimicrobial activity from cytotoxicity which would be helpful in discovering clinical applications for peptide antibiotics.
authors.affiliation: Department of Microbiology, Vanderbilt University, MCN A5119, Nashville, Tennessee, 37232-2363, USA. james.tam@mcmail.vanderbilt.edu
authors.forename: J P
authors.initials: JP
authors.lastname: Tam
authors.forename: Y A
authors.initials: YA
authors.lastname: Lu
authors.forename: J L
authors.initials: JL
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides; D001419:Bacteria / Q000187:drug effects; D002175:Candida / Q000187:drug effects; D003553:Cystine; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000494:pharmacology; D023082:Defensins; D004220:Disulfides; D015195:Drug Design; D006801:Humans; D008253:Macaca mulatta; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry / Q000494:pharmacology; D012462:Saline Solution, Hypertonic
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D004268:DNA-Binding Proteins; D023082:Defensins; D004220:Disulfides; D010455:Peptides; D010456:Peptides, Cyclic; D011506:Proteins; D012462:Saline Solution, Hypertonic; C057636:tachyplesin peptide, Tachypleus tridentatus; D003553:Cystine