Arginine/Tryptophan‐Rich Cyclic α/β‐Antimicrobial Peptides: The Roles of Hydrogen Bonding and Hydrophobic/Hydrophilic Solvent‐Accessible Surface Areas upon Activity and Membrane Selectivity

Abstract

The bacterial selectivity of an amphiphilic library of small cyclic α/β-tetra-, α/β-penta-, and α/β-hexapeptides rich in arginine/tryptophan (Arg/Trp) residues, which contains asymmetric backbone configurations and differ in hydrophobicity and alternating d,l-amino acids, was investigated against Bacillus subtilis and Escherichia coli. The structural analyses showed that the peptides tend to form assemblies of different shapes. All-l-peptides, especially the most hydrophobic pentamers, were more strongly anti-B. subtilis. With the exception to cyclo(Phe-d-Trp-β hArg-Arg-d-Trp) (Phe=phenylalanine), the peptides had no effects on inner membrane of E. coli, but lyzed the lipopolysaccharide layer according to their activity pattern. The activities adversely changed with a decrease in the number of amide intramolecular hydrogen bonds in assemblies of diastereomeric peptides and the ratio of hydrophobic/hydrophilic solvent-accessible surface areas. The remarkable enhanced entropic contribution for the partitioning of the least conformationally constrained cyclo(Trp-d-Phe-β hTrp-Arg-d-Arg) sequence into the membranes supported the strong self-assembly behavior, therefore making the peptide less penetrable through the E. coli outer layer.

Gramicidin‐S‐Inspired Cyclopeptidomimetics as Potent Membrane‐Active Bactericidal Agents with Therapeutic Potential

“…[9] As a result, the majority of clinical applicable AMPs are used or designed for topical applications only with very few exceptions aimed for systematic applications. [5] To overcome these limitations, many different strategies, including but not limited to structural/ sequence modification, [10][11][12][13] specific delivery system design, [14][15][16][17] "smart" AMPs [18][19][20] and de novo designed antimicrobial peptides/peptidomimetics [21][22][23][24][25][26][27] have been developed to efficiently use AMPs without being hindered by their side-effects. Among these strategies, modification or mimicry of naturally occurring peptides with natural amino acids or unnatural building blocks is an efficient pathway.…”

Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

“…In view of the structural stability, Dathe et al (152) were able to create a series of short cyclic hexapeptides (based on AcRRWWRF-NH 2 ) with enhanced antimicrobial efficacy (up to >16-fold increase) against Bacillus subtilis and E. coli compared to the linear form, though the hemolytic activity was increased by 3-fold (152). It was also found that the antimicrobial activities of those small Arg/Trp-rich cyclic peptides were influenced by the self-assembling behavior of peptides at the bacterial membrane instead of their hydrophobic surface area, amphiphilicity, and ring size (153). In addition, a number of small cyclic D,L-alphapeptides (with six or eight alternating D-and L-form residues) have also demonstrated strong antimicrobial efficacy against Gram-positive and/or Gram-negative bacteria via self-assembly on the bacterial membranes as organic nanotubules, which could increase membrane permeability and disrupt transmembrane ion potentials with resultant cell lysis (154,155).…”

Antimicrobial peptides – Advances in development of therapeutic applications

“…Peptide cyclization with limited conformational flexibility not only provides large surface area, which could enhance membrane-binding affinity but also prevents protease degradation. Until now, there are three common types of cross-linking construction: All-hydrocarbon stapling system [ 184 , 185 ], disulfide bonds and its modification [ [186] , [187] , [188] , [189] ] and lactam-bridge [ [190] , [191] , [192] ] ( Fig. 4 ).…”