Synthesis of biologically active cyclic peptides

Izumiya, Nobuo; Kato, Tsuyoshi; Waki, Michinori

doi:10.1002/bip.1981.360200903

Cited by 37 publications

(43 citation statements)

References 14 publications

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“…The backbone exhibits high definition with a root mean square deviation of 0.610 Ϯ 0.105 Å; however, it is quite flexible at residues 4 and 5 due to the absence of a dihedral restraint for the d-lysine. The backbone dihedrals all fall within the range of values expected for an antiparallel ␤-sheet, with the exception of the turn residues and Lys 4 . The and values for Lys 4 are shifted by 180 o relative to the other strand residues, which is an expected result for the d-amino acid configuration.…”

Section: Nmr Spectroscopy and Structure Determination Of Gs14k4mentioning

confidence: 53%

“…The backbone dihedrals all fall within the range of values expected for an antiparallel ␤-sheet, with the exception of the turn residues and Lys 4 . The and values for Lys 4 are shifted by 180 o relative to the other strand residues, which is an expected result for the d-amino acid configuration. The backbone dihedral angles for the structure generated for GS14K4 in 30% TFE/H 2 O are shown in Table III.…”

Section: Nmr Spectroscopy and Structure Determination Of Gs14k4mentioning

confidence: 53%

“…The search for new molecules has led to the study of naturally occurring antimicrobial peptides as a foundation on which to target the lysis of microorganisms by mechanisms that do not aid in the proliferation of resistant strains (1,2). Molecules based on the 10-residue head-to-tail cyclic peptide gramicidin S (3) have shown considerable promise as potential antibiotics (4). Although the precise mechanism of antimicrobial action is uncertain at present, evidence suggests that peptide accumulation in the bacterial membrane results in a permeability increase and loss of barrier function (2,5,6).…”

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confidence: 99%

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Development of the Structural Basis for Antimicrobial and Hemolytic Activities of Peptides Based on Gramicidin S and Design of Novel Analogs Using NMR Spectroscopy

McInnes¹,

Kondejewski

Hodges

et al. 2000

Journal of Biological Chemistry

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The structures of 14-residue head-to-tail cyclic gramicidin S peptides have been investigated to develop the structural rationale for their antimicrobial and hemolytic profiles. The basis for these studies is GS14 (cyclo-(VKLKVdYPLKVKLdYP)), designed as an extension of the naturally occurring antimicrobial peptide. The structure of GS14 has been determined using NMR methods and was found to exist in a highly amphipathic antiparallel ␤-sheet conformation. Systematic enantiomeric substitutions within the framework of the GS14 peptide were found to decrease the amphipathicity of this molecule. These results indicated that there was a direct correlation between the high amphipathic character and potent hemolytic activity in the diastereomers, whereas an inverse correlation existed between amphipathicity and antimicrobial function. To define the structural consequences of changing the amphipathic nature of GS14 analogs to maximize antimicrobial activity and to minimize hemolysis, NMR structures were determined in water and the membranemimetic solvent trifluoroethanol. The structures show that these attributes are the result of induction of the ␤-sheet character in a membrane environment and the positioning of charged side chains on the hydrophobic face of the cyclic framework, thus decreasing the amphipathicity and directed hydrophobicity of these molecules. Implications for the design of more effective antimicrobials are discussed.

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Section: Nmr Spectroscopy and Structure Determination Of Gs14k4mentioning

confidence: 53%

Section: Nmr Spectroscopy and Structure Determination Of Gs14k4mentioning

confidence: 53%

mentioning

confidence: 99%

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Development of the Structural Basis for Antimicrobial and Hemolytic Activities of Peptides Based on Gramicidin S and Design of Novel Analogs Using NMR Spectroscopy

McInnes¹,

Kondejewski

Hodges

et al. 2000

Journal of Biological Chemistry

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“…From numerous structure-activity studies on both natural and synthetic antimicrobial peptides, a number of factors believed to be important for antimicrobial activitiy have been identified. These include the presence of both hydrophobic and basic residues, as well as a defined secondary structure (␣-helical or ␤-sheet), either preformed or inducible, and an amphipathic nature that segregates basic and hydrophobic residues to opposite sides of the molecule in lipid or lipid-mimicking environments (2)(3)(4)(5).…”

mentioning

confidence: 99%

“…We have utilized the 10 residue head-to-tail cyclic peptide gramicidin S (GS) 1 (12) as the basis of our design for novel antimicrobial agents. GS has the sequence cyclo(Val-Orn-Leu-d-Phe-Pro) 2 and exists in an antiparallel ␤-sheet conformation with the strands fixed in place by two type IIЈ ␤-turns (5,13,14). The ␤-sheet structure gives the molecule a preformed amphipathic nature with four hydrophobic residues (Val and Leu) making up one face of the molecule and two basic Orn residues making up the other face.…”

mentioning

confidence: 99%

Dissociation of Antimicrobial and Hemolytic Activities in Cyclic Peptide Diastereomers by Systematic Alterations in Amphipathicity

Kondejewski¹,

Jelokhani-Niaraki²,

Farmer³

et al. 1999

Journal of Biological Chemistry

236

243

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We have investigated the role of amphipathicity in a homologous series of head-to-tail cyclic antimicrobial peptides in efforts to delineate features resulting in high antimicrobial activity coupled with low hemolytic activity (i.e. a high therapeutic index). The peptide GS14, cyclo(VKLKVd-YPLKVKLd-YP), designed on the basis of gramicidin S (GS), exists in a preformed highly amphipathic ␤-sheet conformation and was used as the base compound for this study. Fourteen diastereomers of GS14 were synthesized; each contained a different single enantiomeric substitution within the framework of GS14. The ␤-sheet structure of all GS14 diastereomers was disrupted as determined by CD and NMR spectroscopy under aqueous conditions; however, all diastereomers exhibited differential structure inducibility in hydrophobic environments. Because the diastereomers all have the same composition, sequence, and intrinsic hydrophobicity, the amphipathicity of the diastereomers could be ranked based upon retention time from reversed-phase high performance liquid chromatography. There was a clear correlation showing that high amphipathicity resulted in high hemolytic activity and low antimicrobial activity in the diastereomers. The latter may be the result of increased affinity of highly amphipathic peptides to outer membrane components of Gram-negative microorganisms. The diastereomers possessing the most favorable therapeutic indices possessed some of the lowest amphipathicities, although there was a threshold value below which antimicrobial activity decreased. The best diastereomer exhibited 130-fold less hemolytic activity compared with GS14, as well as greatly increased antimicrobial activities, resulting in improvement in therapeutic indices of between 1,000-and 10,000-fold for a number of microorganisms. The therapeutic indices of this peptide were between 16-and 32-fold greater than GS for Gram-negative microorganisms and represents a significant improvement in specificity over GS. Our findings show that a highly amphipathic nature is not desirable in the design of constrained cyclic antimicrobial peptides and that an optimum amphipathicity can be defined by systematic enantiomeric substitutions.

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All-L-Leu-Pro-Leu-Pro: a challenging cyclization

et al. 2000

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In this paper, we report the difficult synthesis of cyclo(Leu‐Pro‐Leu‐Pro). While the cyclization of Leu‐Pro‐Leu‐D‐Pro did not cause problems, the all‐L‐peptide afforded cyclodimer rather than cyclotetrapeptide (cyclomonomer). A first attempt using our reversible backbone substitution methodology failed. However, we were successful in obtaining the desired cyclo(Leu‐Pro‐Leu‐Pro) by decreasing the concentration. The ratio of cyclomonomer to cyclodimer was raised to 1:1.1 using BOP and 1:0.6 using HATU under our high dilution condition. The structures of the cyclopeptides were confidently assigned by electrospray ionization mass spectrometry and NMR. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.

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Synthesis of biologically active cyclic peptides

Cited by 37 publications

References 14 publications

Development of the Structural Basis for Antimicrobial and Hemolytic Activities of Peptides Based on Gramicidin S and Design of Novel Analogs Using NMR Spectroscopy

Development of the Structural Basis for Antimicrobial and Hemolytic Activities of Peptides Based on Gramicidin S and Design of Novel Analogs Using NMR Spectroscopy

Dissociation of Antimicrobial and Hemolytic Activities in Cyclic Peptide Diastereomers by Systematic Alterations in Amphipathicity

All-L-Leu-Pro-Leu-Pro: a challenging cyclization

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