Inverted analogs of the antibiotic gramicidin S with an improved biological profile

A series of gramicidin S derivatives 4-15 are presented that have four ornithine residues as polar protonated side chains and two central hydrophobic amino acids with unaltered turn regions. These peptides were screened against human erthrocytes and our standard panel of Gram negative- and Gram positive bacteria, including four MRSA strains....

Ring-extended gramicidin S analogs Containing cis δ-sugar amino acid turn mimetics with varying ring size

This article presents a series of ring-extended gramicidin S derivatives, 9-14, that have four ornithine residues as polar protonated side chains and one modified turn region containing a mono-functionalized cis-δ-oxetane, δ-furanoid, or δ-pyranoid sugar amino acid residue. Of the GS analogs evaluated, we identified compound 7, which contains...

Synthesis and evaluation of strand and turn modified ring-extended gramicidin S derivatives

In this paper, we describe the crystal structure of previously reported ring-extended gramicidin S (GS) derivative 2 (GS14K4), containing a d-amino acid residue in one of the β-strand regions. This structure is in agreement with a previously reported modeling study of the same molecule. The polar side chain of the additional d-amino acid residue...

Exploring the conformational and biological versatility of ß-turn-modified gramicidin s by using sugar amino acid homologues that vary in ring size

Monobenzylated sugar amino acids (SAAs) that differ in ether ring size (containing an oxetane, furanoid, and pyranoid ring) were synthesized and incorporated in one of the ß-turn regions of the cyclo-decapeptide gramicidin S (GS). CD, NMR spectroscopy, modeling, and X-ray diffraction reveal that the ring size of the incorporated SAA moieties...

Evaluation of readily accessible azoles as mimics of the aromatic ring of D-phenylalanine in the turn region of gramicidin S

The influence of replacing the d-phenylalanine residue with substituted and unsubstituted azoles on the structure and biological activity of the antibiotic gramicidinS was investigated against a representative panel of Gram-positive and Gram-negative bacteria strains. Substituted triazole derivatives, obtained using a convergent synthetic...

Gramicidin S derivatives containing cis- and trans-morpholine amino acids (MAAS) as turn mimetics

The cyclic decapeptide gramicidin S (GS) was used as a model for the evaluation of four turn mimetics. For this purpose, one of the D-Phe-Pro two-residue turn motifs in the rigid cyclic β-hairp0in structure of GS was replaced with morpholine amino acids (MAA 2-5), differing in stereochemistry and length of the side-chain. The conformational...

An adamantyl amino acid containing gramicidin S analogue with broad spectrum antibacterial activity and reduced hemolytic activity

The cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilic derivatives of GS with either two or four positive charges and characteristics ranging between very polar and very hydrophobic. Screening of this...

Tuning hydrophobicity of highly cationic tetradecameric Gramicidin S analogues using adamantane amino acids

Ring extended Gramicidin S analogues containing adamantane amino acids and six cationic residues were designed and evaluated. Systematic replacement of the hydrophobic residues with adamantane amino acids resulted in a small set of compounds with varying amphipathic character. It was found that the amphipathicity of these compounds is correlated...

Synthesis and biological evaluation of novel gramicidin s analogues

The synthesis of three new analogues of the cyclic cationic antimicrobial peptide Gramicidin S is described. These derivatives contain a modified turn region in which the DPhe-Pro motif has been replaced by a constrained furanoid sugar amino acid or a flexible linear aminoethoxy acetic acid moiety. Structural analysis revealed conformational...

Synthesis and biological evaluation of asymmetric gramicidin S analogues containing modified d-phenylalanine residues

The synthesis of new analogues of the cationic antimicrobial peptide gramicidin S, having a modified d-phenylalanine residue, their antibacterial properties against several Gram positive and negative strains, as well as their hemolytic activity is reported. © 2009 Elsevier Ltd. All rights reserved.

Ring-extended derivatives of gramicidin S with furanoid sugar amino acids in the turn region have enhanced antimicrobial activity

(Chemical Equation Presented) A series of ring-extended gramicidin S (GS) derivatives containing furanoid sugar amino acids were evaluated. Although the extended GS derivatives have a less well-defined secondary structure as determined by NMR and CD, some derivatives show an improved biological profile, namely, an increased antibacterial...

Structural and biological evaluation of some loloatin C analogues

Loloatin C is a cyclic cationic antimicrobial peptide which is active against Gram positive as well as certain Gram negative bacteria. Unfortunately, it is equally potent against human erythrocytes. To probe the structure-activity relationship of this promising antibiotic peptide, amino acid substitution and/or incorporation of a constraint...

Design, synthesis, and evaluation of sugar amino acid based inhibitors of protein prenyl transferases PFT and PGGT-1

Eleven analogues of the C-terminal Ca1a2X motif found in natural substrates of the prenyl transferases PFT and PGGT-1 were synthesized and evaluated for their inhibition potency and selectivity against PFT and PGGT-1. Replacement of the central dipeptide part a1a 2 by a benzylated sugar amino acid resulted in a good and highly selective PFT...

Inhibitors of protein: Arnesyl transferase and protein:geranylgeranyl transferase I : Synthesis of homologous diphosphonate analogs of isoprenylated pyrophosphate

Novel diphosphonate homologs 7a-7c, and their cyclic counterparts 8a- 8c, of the previously synthesized farnesyl pyrophosphate analogs 1 and 2 were prepared and tested for their inhibition potency and specificity of the enzymes PFT and PGGT-I. Compound 2 was shown to be the most potent inhibitor of PFT (1C50=0.58 ± 0.45 μM) in this series. The...