Structure–activity relationships of gramicidin S analogs containing (β-3-pyridyl)-α,β-dehydroalanine residues on membrane permeability

Abstract

The synthesis, biological activities and membrane permeability of gramicidin S (GS) analogs containing (Z)-(b-3-pyridyl)-a,b-dehydroalanine (D Z 3Pal) residues are described. The cationic side chains of the Orn and D Z 3Pal 4,4 0 residues in [D Z 3Pal 4,4 0 ]GS (1) are important for dissociating antimicrobial and hemolytic activity.

Recent Advances in the Exploration of Therapeutic Analogues of Gramicidin S, an Old but Still Potent Antimicrobial Peptide

“…A plausible explanation for the benefits of this orientation is the existence of cation−π interactions between the aromatic ring of d -Tic and the δ-NH 3 + of the Orn side chain favoring penetration of the peptide into the cell membrane. A similar study was made by Yamada et al, who synthesized a series of dehydropeptides with preserved β-sheet character. , The most promising peptide, 10 (Table ), combines an antimicrobial activity comparable to that of wild-type GS with a considerably reduced hemolytic activity. However, an in-depth discussion about the orientation of aromatic rings is absent.…”

“…A similar study was made by Yamada et al, who synthesized a series of dehydropeptides with preserved β-sheet character. 47,48 The most promising peptide, 10 (Table 5), combines an antimicrobial activity comparable to that of wildtype GS with a considerably reduced hemolytic activity. However, an in-depth discussion about the orientation of aromatic rings is absent.…”

Late‐Stage Installation of Dehydroamino Acid Motifs into Peptides Enabled by an N‐Chloropeptide Strategy

“…After these pioneering studies, numerous reports of the structure‐activity relationships (SARs) of ΔAA‐containing peptides were published [3] . For instance, gramicidin S (GS) is a membrane‐lytic cyclic peptide antibiotic against both Gram‐positive and Gram‐negative bacteria; the installation of ΔAA motifs into the structure of GS provided an improved analogue that exhibits high solubility in water and low hemolytic activity [3a,d] . Owing to the importance of ΔAAs, as described above, various transformations to install ΔAA structures have recently been explored [1a,c,4–7] …”

Stabilization of Cyclic β-Hairpins by Ugi-Reaction-Derived N-Alkylated Peptides: The Quest for Functionalized β-Turns

“…We chose the antibacterial cyclic decapeptide Gramicidin S (GS, cyclo­(Pro-Val-Orn-Leu- d -Phe) 2 ) as the model compound for β-sheet conformational mimicry . Whereas our goal is not to develop novel antibacterials, GS is considered as a prototypical β-hairpin compound, and its structure has been previously used to design novel peptidomimetics − and sugar amino acid turn inducers (Figure A). GS is a C2-symmetric β-hairpin in which two antiparallel β-strands are connected by two type-II′ β-turns induced by the dipeptide d -Phe-Pro.…”