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

Solanas, Concepción; Torre, Beatriz G. de la; Fernández‐Reyes, María José; Santiveri, Clara M.; Jiménez, María Ángeles Sánchez; Rivas, Luís; Jiménez, Ana I.; Andreu, David; Cativiela, Carlos

doi:10.1021/jm800886n

Cited by 53 publications

(61 citation statements)

References 72 publications

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“…To determine bacterial selectivity of the peptides, we calculated their therapeutic index (TI) as a measure of the relative safety of the drug. [31][32][33] The TI of the peptides was calculated as the ratio of the HC50 that produced 50% hemolysis against human red blood cells to the average MIC value against six selected microorganisms. Larger values of TI correspond to greater bacterial selectivity.…”

Section: Resultsmentioning

confidence: 99%

A Novel Trp-rich Model Antimicrobial Peptoid with Increased Protease Stability

Bang

Nan²,

Lee³

et al. 2010

Bulletin of the Korean Chemical Society

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In order to increase protease stability of a novel Trp-rich model antimicrobial peptide, K6L2W3 (KLWKKWKKWLK-NH2) and investigate the effect of L-amino acid to peptoid residue conversion on biological functions, we synthesized its antimicrobial peptoid, k6l2w3. Peptoid k6l2w3 had similar bacterial selectivity compared to peptide K6L2W3. The bactericidal rate of k6l2w3 was somewhat slower than that of K6L2W3. Peptoid k6l2w3 exhibited very little dye leakage from bacterial outer-membrane mimicking PE/PG liposomes, as observed in K6L2W3, indicating that the major target site of K6L2W3 and k6l2w3 may be not the cell membrane but the cytoplasm of bacteria. Trypsin treatment of K6L2W3 completely abolished antimicrobial activities against Escherichia coli and Staphylococcus aureus. In contrast, the antimicrobial activity of k6l2w3 was completely preserved after trypsin treatment. Taken together, our results suggested that antimicrobial peptoid k6l2w3 can potentially serves as a promising therapeutic agent for the treatment of microbial infection.

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Section: Resultsmentioning

confidence: 99%

A Novel Trp-rich Model Antimicrobial Peptoid with Increased Protease Stability

Bang

Nan²,

Lee³

et al. 2010

Bulletin of the Korean Chemical Society

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“…The prokayotic selectivity of the peptides is defined by the concept of the therapeutic index (TI) as a measure of the relative safety of the drug. [24][25][26] The TI of each peptide was calculated as the ratio of the MHC (minimal hemolytic concentration) value to the GM (geometric mean of MICs against six selected microorganisms). When there was significant no hemolysis at the highest concentration tested (100 μM), 200 μM was used for the TI calculation, since the test was carried out by two-fold serial dilution.…”

Section: Resultsmentioning

confidence: 99%

Prokaryotic Selectivity, Anti-endotoxic Activity and Protease Stability of Diastereomeric and Enantiomeric Analogs of Human Antimicrobial Peptide LL-37

Nan¹,

Lee²,

Shin

2012

Bulletin of the Korean Chemical Society

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LL-37 is the only antimicrobial peptide (AMP) of the human cathelicidin family. In addition to potent antimicrobial activity, LL-37 is known to have the potential to inhibit lipolysaccharide (LPS)-induced endotoxic effects. To provide the stability to proteolytic digestion and increase prokaryotic selectivity and/or antiendotoxic activity of two Lys/Trp-substituted 19-meric antimicrobial peptides (a4-W1 and a4-W2) designed from IG-19 (residues 13-31 of LL-37), we synthesized the diastereomeric peptides (a4-W1-D and a4-W2-D) with D-amino acid substitution at positions 3, 7, 10, 13 and 17 of a4-W1 and a4-W2, respectively and the enantiomeric peptides (a4-W1-E and a4-W2-E) composed D-amino acids. The diastereomeric peptides exhibited the best prokaryotic selectivity and effective protease stability, but no or less anti-endotoxic activity. In contrast, the enantiomeric peptides had not only prokaryotic selectivity and anti-endotoxic activity but also protease stability. Our results suggest that the hydrophobicity and α-helicity of the peptide is important for antiendotoxic activity. In particular, the enantiomeric peptides showed potent anti-endotoxic and LPS-neutralizing activities comparable to that of LL-37. Taken together, both a4-W1-E and a4-W2-E holds promise as a template for the development of peptide antibiotics for the treatment of endotoxic shock and sepsis.

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“…D-Phe and D-Trp elicit a chemotactic response in human neutrophils via activation of a G protein-coupled receptor (IrukayamaTomobe et al 2009). D-Phe analogs enhance the antibiotic profile of the antimicrobial peptide gramicidin (Solanas et al 2009). D-Phe and hydroxyproline define the native structure and presumably virulence of conotoxin, a toxic peptide obtained from the venom produced by cone snails (Huang and Du 2009).…”

Section: D-phenylalaninementioning

confidence: 99%

Nutritional and medicinal aspects of d-amino acids

2011

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This paper reviews and interprets a method for determining the nutritional value of D-amino acids, D-peptides, and amino acid derivatives using a growth assay in mice fed a synthetic all-amino acid diet. A large number of experiments were carried out in which a molar equivalent of the test compound replaced a nutritionally essential amino acid such as L-lysine (L-Lys), L-methionine (L-Met), L-phenylalanine (L-Phe), and L-tryptophan (L-Trp) as well as the semi-essential amino acids L-cysteine (L-Cys) and L-tyrosine (L-Tyr). The results show wide-ranging variations in the biological utilization of test substances. The method is generally applicable to the determination of the biological utilization and safety of any amino acid derivative as a potential nutritional source of the corresponding L-amino acid. Because the organism is forced to use the D-amino acid or amino acid derivative as the sole source of the essential or semi-essential amino acid being replaced, and because a free amino acid diet allows better control of composition, the use of all-amino-acid diets for such determinations may be preferable to protein-based diets. Also covered are brief summaries of the widely scattered literature on dietary and pharmacological aspects of 27 individual D-amino acids, D-peptides, and isomeric amino acid derivatives and suggested research needs in each of these areas. The described results provide a valuable record and resource for further progress on the multifaceted aspects of D-amino acids in food and biological samples.

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

Cited by 53 publications

References 72 publications

A Novel Trp-rich Model Antimicrobial Peptoid with Increased Protease Stability

A Novel Trp-rich Model Antimicrobial Peptoid with Increased Protease Stability

Prokaryotic Selectivity, Anti-endotoxic Activity and Protease Stability of Diastereomeric and Enantiomeric Analogs of Human Antimicrobial Peptide LL-37

Nutritional and medicinal aspects of d-amino acids

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