title: Rational design of alpha-helical antimicrobial peptides: do's and don'ts.
abstract: Antimicrobial peptides (AMPs) are promising candidates for battling multiresistant bacteria. Despite extensive research, structure-activity relationships of AMPs are not fully understood, and there is a lack of structural data relating to AMPs in lipids. Here we present the NMR structure of anoplin (GLLKRIKTLL-NH2 ) in a micellar environment. A vast library of substitutions was designed and tested for antimicrobial and hemolytic activity, as well as for changes in structure and lipid interactions. This showed that improvement of antimicrobial activity without concomitant introduction of strong hemolytic activity can be achieved through subtle increases in the hydrophobicity of the hydrophobic face or through subtle increases in the polarity of the hydrophilic face of the helix, or-most efficiently-a combination of both. A set of guidelines based on the results is given, for assistance in how to modify cationic α-helical AMPs in order to control activity and selectivity. The guidelines are finally tested on a different peptide.
authors.affiliation: Department of Chemistry and Bioscience, Aalborg University, Frederik Bajers vej 7H, 9220 Aalborg Ø (Denmark).
authors.forename: Lars Erik
authors.initials: LE
authors.lastname: Uggerhøj
authors.forename: Tanja Juul
authors.initials: TJ
authors.lastname: Poulsen
authors.forename: Jens Kristian
authors.initials: JK
authors.lastname: Munk
authors.forename: Marlene
authors.initials: M
authors.lastname: Fredborg
authors.forename: Teis Esben
authors.initials: TE
authors.lastname: Sondergaard
authors.forename: Niels
authors.initials: N
authors.lastname: Frimodt-Moller
authors.forename: Paul Robert
authors.initials: PR
authors.lastname: Hansen
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wimmer
mesh_terms: D000595:Amino Acid Sequence; D029845:Amphibian Proteins / Q000737:chemistry; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004912:Erythrocytes / Q000187:drug effects; D053878:Hemolytic Agents / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012995:Solubility; D013329:Structure-Activity Relationship; D014862:Wasp Venoms / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D029845:Amphibian Proteins; D023181:Antimicrobial Cationic Peptides; D053878:Hemolytic Agents; D008823:Micelles; D014862:Wasp Venoms; C443041:anoplin; C121829:citropin 1.1 protein, Litoria
keywords: NMR spectroscopy; anoplin; antimicrobial peptides; paramagnetic relaxation enhancement; structure-activity relationships