Conformational states and biological activity of cyclic peptides

Ovchinnikov, Yu.A.; Иванов, В. Т.

doi:10.1016/0040-4020(75)80216-x

Cited by 270 publications

(109 citation statements)

References 372 publications

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“…In this context, Ovchinnikov & Ivanov (1976) mentioned the proximity of the distance between the NE atoms of the two ornithine residues in the gramicidin S molecule, established by the spectral methods, to the negative charges on the phosphate groups in the phospholipid membranes. The possibility of the creation of the gramicidin S channels was noted by some authors (Sholtz, Solovjeva & Kotelnikova, 1975;Sholtz, 1979;Reznik, 1982), who studied the action of the antibiotic on mitochondrial membranes, though no assumptions were made about the structure of these channels.…”

Section: Discussionmentioning

confidence: 99%

Channels in the Gramicidin S-with-Urea Structure and their Possible Relation to Transmembrane Ion Transport

Tishchenko¹,

Andrianov²,

Vainstein³

et al. 1997

Acta Cryst D

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The structure of membrane-active antibiotic cyclodecapeptide gramicidin S in the crystals of its complex with urea, C60H92N12010.0.5[(NH2)2CO ].7.94H20 , has been investigated with three-dimensional X-ray data by the automatic sequential approximation method. The crystals are trigonal, space group P3121, a = 25.80(3), c--21.49(2)A, M r = 7968, calculated density = 1.088mg m -3, Z = 1. Conventional R factor: R1 = 0.0943, wR2 = 0.2478

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Section: Discussionmentioning

confidence: 99%

Channels in the Gramicidin S-with-Urea Structure and their Possible Relation to Transmembrane Ion Transport

Tishchenko¹,

Andrianov²,

Vainstein³

et al. 1997

Acta Cryst D

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“…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. This amphipathicity, along with high hydrophobicity, has long been thought to be important for the antimicrobial properties of GS-like peptides (5,(15)(16)(17)(18). A previous study with cyclic ␤-sheet antimicrobial peptides based on GS indicated that it is possible to dissociate antimicrobial and hemolytic activities through gross manipulation of ␤-sheet structure and amphipathicity (19).…”

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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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“…Many derivatives of such compounds with a DKP ring include antiviral properties (gliotoxins) and powerful antibiotic and anti-tumor agents, such as amphomycin and bicyclomycin (Prasad, 1995). Furthermore, certain cyclic dipeptides have been shown to have antiviral, antibiotic, and anti-tumor properties (Ovchinnikov and Ivanov, 1975).…”

mentioning

confidence: 99%

Isolation and characterization of Streptomyces sp. KH-614 producing anti-VRE (vancomycin-resistant enterococci) antibiotics.

Rhee

2002

J. Gen. Appl. Microbiol.

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Conformational states and biological activity of cyclic peptides

Cited by 270 publications

References 372 publications

Channels in the Gramicidin S-with-Urea Structure and their Possible Relation to Transmembrane Ion Transport

Channels in the Gramicidin S-with-Urea Structure and their Possible Relation to Transmembrane Ion Transport

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

Isolation and characterization of Streptomyces sp. KH-614 producing anti-VRE (vancomycin-resistant enterococci) antibiotics.

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