title: Structural requirements for potent versus selective cytotoxicity for antimicrobial dermaseptin S4 derivatives.
abstract: To better understand the structural requirements for selective cytotoxicity of antimicrobial peptides, seven dermaseptin S4 analogs were produced and investigated with respect to molecular organization in solution, binding properties to model phospholipid membranes, and cytotoxic properties. Native dermaseptin S4 displayed high aggregation in solution and high binding affinity. These properties correlated with high cytotoxicity. Yet, potency was progressively limited when facing cells whose plasma membrane was surrounded by increasingly complex barriers. Increasing the positive charge of the native peptide led to partial depolymerization that correlated with higher binding affinity and with virtually non-discriminative high cytotoxicity against all cell types. The C-terminal hydrophobic domain was found responsible for binding to membranes but not for their disruption. Truncations of the C terminus combined with increased positive charge of the N-terminal domain resulted in short peptides having similar binding affinity as the parent compound but displaying selective activity against microbes with reduced toxicity toward human red blood cells. Nuclear magnetic resonance-derived three-dimensional structures of three active derivatives enabled the delineation of a common amphipathic structure with a clear separation of two lobes of positive and negative electrostatic potential surfaces. Whereas the spatial positive electrostatic potential extended considerably beyond the peptide dimensions and was required for potency, selectivity was affected primarily by hydrophobicity. The usefulness of this approach for the design of potent and/or selective cytolytic peptides is discussed herein.
authors.affiliation: Department of Biological Chemistry and The Wolfson Centre for Applied Structural Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, 91904 Jerusalem, Israel. irinak@macbeth.ls.huji.ac.il
authors.forename: Irina
authors.initials: I
authors.lastname: Kustanovich
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Shalev
authors.forename: Masha
authors.initials: M
authors.lastname: Mikhlin
authors.forename: Leonid
authors.initials: L
authors.lastname: Gaidukov
authors.forename: Amram
authors.initials: A
authors.lastname: Mor
mesh_terms: D000595:Amino Acid Sequence; D029845:Amphibian Proteins; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D003455:Cryptococcus neoformans / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000382:microbiology; D006801:Humans; D007700:Kinetics; D018320:Leishmania major; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D013997:Time Factors; D014466:Ultraviolet Rays
chemical_list: D029845:Amphibian Proteins; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D010455:Peptides; C109653:dermaseptin 4 protein, Phyllomedusa