Conformation and membrane activity of an analogue of the peptaibol antibiotic trichogin GA IV with a lipophilic amino acid at the N-terminus

Locardi, Elsa; Mammi, Stefano; Peggion, Evaristo; Monaco, Vania; Formaggio, Fernando; Crisma, Marco; Toniolo, Claudio; Bodo, Bernard; Rebuffat, Sylvie; Kamphuis, J.; Broxterman, Quirinus B.

doi:10.1002/(sici)1099-1387(199809)4:6<389::aid-psc158>3.0.co;2-4

Cited by 21 publications

(6 citation statements)

References 17 publications

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“…A similar conformation was described for the [Leu 11 -OMe] analogue in the same solvent [21]. Mixed 3 10 /a-helical structures were reported for the [Leu 11 -OMe] [23], [Ac-(aMe)Aun 0 , Leu 11 -OMe] [22], [Ser 2,5,6,9 , Leu 11 -OMe] [23] and single TOAC-based [26] trichogin analogues in a number of alcohols and in a membrane-mimetic environment. The helical structure of the Ser analogue is remarkably the least flexible.…”

Section: Three-dimensional Structuresupporting

confidence: 68%

“…Nevertheless, partitioning likely plays a significant role, since incorporating octanoyl groups at both ends of the peptide increases activity [27]. On the other hand, the lytic activity is not sensitive to small changes in the location of the lipidic group, since moving the acyl chain from the N-terminal amino group of trichogin to the side chain of residue 1 results in similar membrane lytic activity [22]. There may also be other roles for the acyl group, including orienting the peptide in the membrane in a particular manner, or the acyl chain itself may contribute to the destabilization of the membrane.…”

Section: Membrane Activitymentioning

confidence: 99%

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Lipopeptaibols, a novel family of membrane active, antimicrobial peptides

Toniolo¹,

Crisma²,

Formaggio³

et al. 2001

CMLS, Cell. Mol. Life Sci.

141

131

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Lipopeptaibols are members of a novel group of naturally occurring, short peptides with antimicrobial activity, characterized by a lipophilic acyl chain at the N-terminus, a high content of the turn/helix forming alpha-aminoisobutyric acid and a 1,2-amino alcohol at the C-terminus. The amino acid sequences range from 6 to 10 residues and the fatty acyl moieties from 8 to 15 carbon atoms. The peptide portion of lipopeptaibols can be shorter than those of the nonlipidated peptaibols that range from 10 to 19 amino acid residues. The longest peptides fold into a mixed 3(10)/alpha helix, whereas the shortest peptides tend to adopt a beta-turn/sheet structure. Using solution methodologies, a series of analogues of trichogin GA IV was synthesized which allowed determination of the minimal lipid chain and peptide main-chain lengths for the onset of membrane activity and exploitation of a number of spectroscopic techniques aimed at determining its preferred conformation under a variety of conditions and investigating in detail its mode of interaction with, and its effect on, the phospholipid membranes.

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Section: Three-dimensional Structuresupporting

confidence: 68%

Section: Membrane Activitymentioning

confidence: 99%

Lipopeptaibols, a novel family of membrane active, antimicrobial peptides

Toniolo¹,

Crisma²,

Formaggio³

et al. 2001

CMLS, Cell. Mol. Life Sci.

141

131

View full text Add to dashboard Cite

show abstract

“…NH i+3 , and C a H i ! NH i+4 cross peaks are seen, which account for a mixed 3 10 -/a-helical conformation, such as those already reported for natural trichogin GA IV and some of its analogs [16,21,22,26]. However, the spectrum is characterized by a number of weak signals, probably because of the concomitant presence of a minor, perhaps less preferred, peptide conformation.…”

Section: Conformational Studiessupporting

confidence: 57%

Spectroscopically labeled peptaibiotic analogs: the 4‐nitrophenylalanine infrared absorption probe inserted at different positions into trichogin GA IV

Peggion

Biondi

Zotti

et al. 2012

Journal of Peptide Science

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A set of three analogs of the 10-residue, membrane-active lipopeptaibiotic trichogin GA IV, labeled with the promising 4-nitrophenylalanine IR absorption probe for local polarity, was synthesized by the solid-phase methodology, chromatographically purified, and extensively characterized. A single residue modification was inserted near the N-terminus, in the central region, or at the C-terminus. A solution conformational analysis, carried out by FT-IR absorption, CD, and 2D-NMR combined with molecular dynamics calculations, indicates that the mono-labeled analogs maintain the overall helical properties of the parent compound. Membrane permeabilization measurements and antimicrobial tests revealed that they possess membrane-modifying properties and in vitro antibacterial activities analogous to those of the natural lipopeptaibiotic. Our IR absorption and attenuated total reflectance investigations in various environments, from which water was excluded for solubility reasons, showed that the 1350 cm(-1) 4-nitrobenzyl band is a reporter group of rather limited sensitivity.

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“…These results parallel closely those already published for natural trichogin GA IV and its [Leu 11 -OMe] analog. 12,15,16,18 Fig. 2 also shows the spectra (peptide concentration: 1.0 mM) of the shorter segments C(1-4) and B-A (5)(6)(7)(8)(9)(10)(11) utilized for the synthesis of the N e -Lys Z-protected K2-OMe (part A), and E(1-4) and E-B(1-8) employed to prepare the N e -Lys Z-protected K9-OMe (part B).…”

Section: Conformational Analysismentioning

confidence: 99%

Trichogin GA IV: A versatile template for the synthesis of novel peptaibiotics

et al. 2012

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Trichogin GA IV, isolated from the fungus Trichoderma longibrachiatum, is the prototype of lipopeptaibols, the sub-class of short-length peptaibiotics exhibiting membrane-modifying properties. This peptaibol is predominantly folded in a mixed 3(10)-/α- helical conformation with a clear, albeit modest, amphiphilic character, which is likely to be responsible for its capability to perturb bacterial membranes and to induce cell death. In previous papers, we reported on the interesting biological properties of trichogin GA IV, namely its good activity against Gram positive bacteria, in particular methicillin-resistant S. aureus strains, its stability towards proteolytic degradation, and its low hemolytic activity. Aiming at broadening the antimicrobial activity spectrum by increasing the peptide helical amphiphilicity, in this work we synthesized, by solution and solid-phase methodologies, purified and fully characterized a set of trichogin GA IV analogs in which the four Gly residues at positions 2, 5, 6, 9, lying in the poorly hydrophilic face of the helical structure, are substituted by one (position 2, 5, 6 or 9), two (positions 5 and 6), three (positions 2, 5, and 9), and four (positions 2, 5, 6, and 9) Lys residues. The conformational preferences of the Lys-containing analogs were assessed by FT-IR absorption, CD and 2D-NMR techniques in aqueous, organic, and membrane-mimetic environments. Interestingly, it turns out that the presence of charged residues induces a transition of the helical conformation adopted by the peptaibols (from 3(10)- to α-helix) as a function of pH in a reversible process. The role played in the analogs by the markedly increased amphiphilicity was further tested by fluorescence leakage experiments in model membranes, protease resistance, antibacterial and antifungal activities, cytotoxicity, and hemolysis. Taken together, our biological results provide evidence that some of the least substituted among these analogs are good candidates for the development of new membrane-active antimicrobial agents.

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Conformation and membrane activity of an analogue of the peptaibol antibiotic trichogin GA IV with a lipophilic amino acid at the N-terminus

Cited by 21 publications

References 17 publications

Lipopeptaibols, a novel family of membrane active, antimicrobial peptides

Lipopeptaibols, a novel family of membrane active, antimicrobial peptides

Spectroscopically labeled peptaibiotic analogs: the 4‐nitrophenylalanine infrared absorption probe inserted at different positions into trichogin GA IV

Trichogin GA IV: A versatile template for the synthesis of novel peptaibiotics

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