Replacement of phenylalanine in gramicidin S by other amino acids

Aarstad, Kjell; Zimmer, T.L.; Laland, S.

doi:10.1016/0014-5793(79)81263-6

Cited by 5 publications

(4 citation statements)

References 7 publications

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“…The quintessential example of this situation is GS, whose type II′ β-turns have been a testing ground for extensive d -Phe-Pro replacements by a variety of peptidomimetics, with variable success (see Introduction and refs − ,− ). In comparison, fewer studies have addressed the substitution of either l -Pro , or d -Phe ,,− by appropriate surrogates. The goal of this work was to explore and structurally interpret the fine-tuning of GS antibiotic activity by replacement of d -Phe with a novel set of noncoded aromatic d -amino acids already tested as turn-promoters.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Index of Gramicidin S is Strongly Modulated by d-Phenylalanine Analogues at the β-Turn

et al. 2009

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Analogues of the cationic antimicrobial peptide gramicidin S (GS), cyclo (Val-Orn-Leu-D-PhePro) 2 , with D-Phe residues replaced by different (restricted mobility, mostly) surrogates have been synthesized and used in SAR studies against several pathogenic bacteria. While all D-Phe substitutions are shown by NMR to preserve the overall β-sheet conformation, they entail subtle structural alterations that lead to significant modifications in biological activity. In particular, the analogue incorporating D-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) shows a modest but significant increase in therapeutic index, mostly due to a sharp decrease in hemolytic effect. The fact that NMR data show a shortened distance between the D-Tic aromatic ring and the Orn δ-amino group may help explain the improved antibiotic profile of this analogue.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Index of Gramicidin S is Strongly Modulated by d-Phenylalanine Analogues at the β-Turn

et al. 2009

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“…Gramicidin S (GS) is an antimicrobial peptide that has been the subject of numerous structure–activity studies (2–12). It is active against both gram‐negative and gram‐positive bacteria (13), but has had limited applications as a therapeutic antimicrobial agent because of its high toxicity to human cells.…”

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confidence: 99%

“…Therefore, killing is rapid (minutes vs. hours or days) fairly nonspecific (active against a broad spectrum of gram-positive and gram-negative bacteria) and does not produce bacteria resistant to this mode of action (7). Gramicidin S (GS) is an antimicrobial peptide that has been the subject of numerous structure-activity studies (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). It is active against both gram-negative and grampositive bacteria (13), but has had limited applications as a therapeutic antimicrobial agent because of its high toxicity to human cells.…”

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confidence: 99%

“…The issue has brought attention to the need for alternative antimicrobial agents that bacteria have not or are unlikely to develop resistance mechanisms against. In the past two decades, a number of naturally occurring cationic antimicrobial peptides have been identified and characterized in a wide range of organisms (2–5). In contrast with conventional antibiotics that specifically inhibit essential molecules such as enzymes involved in cell wall synthesis, transcription or translation, these peptides are thought to directly interact with and disrupt the stability of the microbial membrane (6).…”

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confidence: 99%

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Effects of single d‐amino acid substitutions on disruption of β‐sheet structure and hydrophobicity in cyclic 14‐residue antimicrobial peptide analogs related to gramicidin S

Lee

Powers

Pflegerl

et al. 2004

The Journal of Peptide Research

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Gramicidin S (GS) is a 10-residue cyclic beta-sheet peptide with lytic activity against the membranes of both microbial and human cells, i.e. it possesses little to no biologic specificity for either cell type. Structure-activity studies of de novo-designed 14-residue cyclic peptides based on GS have previously shown that higher specificity against microbial membranes, i.e. a high therapeutic index (TI), can be achieved by the replacement of a single L-amino acid with its corresponding D-enantiomer [Kondejewski, L.H. et al. (1999) J. Biol. Chem. 274, 13181]. The diastereomer with a D-Lys substituted at position 4 caused the greatest improvement in specificity vs. other L to D substitutions within the cyclic 14-residue peptide GS14, through a combination of decreased peptide amphipathicity and disrupted beta-sheet structure in aqueous conditions [McInnes, C. et al. (2000) J. Biol. Chem. 275, 14287]. Based on this information, we have created a series of peptide diastereomers substituted only at position 4 by a D- or L-amino acid (Leu, Phe, Tyr, Asn, Lys, and achiral Gly). The amino acids chosen in this study represent a range of hydrophobicities/hydrophilicities as a subset of the 20 naturally occurring amino acids. While the D- and L-substitutions of Leu, Phe, and Tyr all resulted in strong hemolytic activity, the substitutions of hydrophilic D-amino acids D-Lys and D-Asn in GS14 at position 4 resulted in weaker hemolytic activity than in the L-diastereomers, which demonstrated strong hemolysis. All of the L-substitutions also resulted in poor antimicrobial activity and an extremely low TI, while the antimicrobial activity of the D-substituted peptides tended to improve based on the hydrophilicity of the residue. D-Lys was the most polar and most efficacious substitution, resulting in the highest TI. Interestingly, the hydrophobic D-amino acid substitutions had superior antimicrobial activity vs. the L-enantiomers although substitution of a hydrophobic D-amino acid increases the nonpolar face hydrophobicity. These results further support the role of hydrophobicity of the nonpolar face as a major influence on microbial specificity, but also highlights the importance of a disrupted beta-sheet structure on antimicrobial activity.

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Nucleic Acid Independent Synthesis of Peptides

Kleinkauf

Döhren

1981

Current Topics in Microbiology and Immunology

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Replacement of phenylalanine in gramicidin S by other amino acids

Cited by 5 publications

References 7 publications

Therapeutic Index of Gramicidin S is Strongly Modulated by d-Phenylalanine Analogues at the β-Turn

Therapeutic Index of Gramicidin S is Strongly Modulated by d-Phenylalanine Analogues at the β-Turn

Effects of single d‐amino acid substitutions on disruption of β‐sheet structure and hydrophobicity in cyclic 14‐residue antimicrobial peptide analogs related to gramicidin S

Nucleic Acid Independent Synthesis of Peptides

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