Alpha-helical antimicrobial peptides—Using a sequence template to guide structure–activity relationship studies

Abstract

An important class of cytolytic antimicrobial peptides (AMPs) assumes an amphipathic, alpha-helical conformation that permits efficient interaction with biological membranes. Host defence peptides of this type are widespread in nature, and numerous synthetic model AMPs have been derived from these or designed de novo based on their characteristics. In this review we provide an overview of the 'sequence template' approach which we have used to design potent artificial helical AMPs, to guide structure-activity relationship studies aimed at their optimization, and to help identify novel natural AMP sequences. Combining this approach with the rational use of natural and non-proteinogenic amino acid building blocks has allowed us to probe the individual effects on the peptides' activity of structural and physico-chemical parameters such as the size, propensity for helical structuring, amphipathic hydrophobicity, cationicity, and hydrophobic or polar sector characteristics. These studies furthermore provided useful insights into alternative modes of action for natural membrane-active helical peptides.

Peptide synthesis, characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infection imaging with PET/CT

“…Amphipathic alpha helices, such as UBI29-41, are generally considered less challenging to chemically synthesize than beta sheet or disulfide rich peptides [35]. A thorough search of the literature did not yield any conclusive reasons as to why the N-terminal-threonine should be an especially problematic residue to couple under the conditions used in this study [6,24,28,36,37], although it is possible that steric hindrance effects, due to its bulky side chain, may have prevented its coupling onto the nascent peptide [38].…”

Alpha-helical cationic antimicrobial peptides: relationships of structure and function

“…For a given peptide, the hemolytic activity is represented by the maximum peptide concentration with no hemolysis (MHC). In contrast, the antimicrobial activity is represented by the minimum peptide concentration that inhibits bacterial growth (MIC), as determined by either microbroth serial dilution or radial diffusion assays (Zelezetsky and Tossi, 2006). The clinical potential of a given AMP is assessed by the ratio of MHC and MIC, or therapeutic index.…”

Surface Physical Activity and Hydrophobicity of Designed Helical Peptide Amphiphiles Control Their Bioactivity and Cell Selectivity

“…Interestingly, more than 70% of naturally occurring AMPs start with Gly residue in the N-terminus, which is thought to resist enzyme degradation. 7 To better understand the effects of the terminal modifications of G(IIKK) 3 I-NH 2 on antitumor activity and to develop new variants with enhanced cell selectivity, we have designed two series of new peptides containing different capping groups at both termini, as shown in Table 1. Specifically, the N-terminal Gly or C-terminal Ile residue of G(IIKK) 3 I-NH 2 was replaced by 1) hydrophobic amino acids Ala and Val, both of which are more hydrophobic than Gly but less hydrophobic than Ile;…”

“…Although ACPs exhibit many desirable properties such as broad spectrum activity, high structural stability and low probability of inducing resistance, [3][4][5] their development as novel anticancer agents is hampered by their poor bioavailability, potential immunogenicity, cytotoxicity to host cells and high production costs. 4,6 To circumvent these problems, researchers have tried to develop novel synthetic ACPs, e.g., by sequence modifications from naturally occurring template peptides, 2,7 by D-amino acid substitution at the nonpolar surface, 8,9 and by shortening peptide sequences to reduce cost. 1,10,11 In the course of structural design for optimal ACPs, properties including sequence, length, net charge, secondary structure, amphipathicity and hydrophobicity must be carefully examined.…”