title: Properties and structure-activity studies of cyclic beta-hairpin peptidomimetics based on the cationic antimicrobial peptide protegrin I.
abstract: The properties and structure-activity relationships (SAR) of a macrocyclic analogue of porcine protegrin I (PG-I) have been investigated. The lead compound, having the sequence cyclo-(-Leu-Arg-Leu-Lys-Lys-Arg-Arg-Trp-Lys-Tyr-Arg-Val-d-Pro-Pro-), shows antimicrobial activity against Gram-positive and -negative bacteria, but a much lower haemolytic activity and a much reduced ability to induce dye release from phosphatidylcholine/phosphatidylglycerol liposomes, when compared to PG-I. The enantiomeric form of the lead peptide shows comparable antimicrobial activity, a property shared with other cationic antimicrobial peptides acting on cell membranes. SAR studies involving the synthesis and biological profiling of over 100 single site substituted analogues, showed that the antimicrobial activity was tolerant to a large number of the substitutions tested. Some analogues showed slightly improved antimicrobial activities (2-4-fold lowering of MICs), whereas other substitutions caused large increases in haemolytic activity on human red blood cells.
authors.affiliation: Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. robinson@oci.unizh.ch
authors.forename: John A
authors.initials: JA
authors.lastname: Robinson
authors.forename: Sasalu C
authors.initials: SC
authors.lastname: Shankaramma
authors.forename: Peter
authors.initials: P
authors.lastname: Jetter
authors.forename: Ursula
authors.initials: U
authors.lastname: Kienzl
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
authors.forename: Jan W
authors.initials: JW
authors.lastname: Vrijbloed
authors.forename: Daniel
authors.initials: D
authors.lastname: Obrecht
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002412:Cations / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011506:Proteins / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D023181:Antimicrobial Cationic Peptides; D002412:Cations; D010456:Peptides, Cyclic; D011506:Proteins; C094880:protegrin-1