Posttranslationally modified bacteriocins—the lantibiotics

Guder, André; Wiedemann, Imke; Sahl, Hans‐Georg

doi:10.1002/1097-0282(2000)55:1<62::aid-bip60>3.0.co;2-y

Cited by 174 publications

(41 citation statements)

References 88 publications

(51 reference statements)

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“…This review will therefore concentrate on strategies for cyclization of peptides which have found favour over the past decade (up to 2002), although the rationale behind some of the developments will be alluded to from a database of over 30 years of specialist reviews in this area [3]. Recent years have seen a significant increase in structural diversity as exemplified by compounds derived from marine sources [4][5][6][7][8], fungi [9][10][11], microorganisms [12][13][14] and higher plants [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

The cyclization of peptides and depsipeptides

Davies

2003

Journal of Peptide Science

417

241

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Constricting the peptide backbone into a more defined conformational form through cyclization is an activity evolved in nature and in synthetic work, the latter straddling only the most recent decades. The resulting conformational constraints increase the probability of an optimum response with bio-receptors. The purpose of this review is to highlight developments that have proved to be reasonably efficient in the macrocyclization of linear precursors into cyclic peptides and depsipeptides.

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Section: Introductionmentioning

confidence: 99%

The cyclization of peptides and depsipeptides

Davies

2003

Journal of Peptide Science

417

241

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“…Amino acid sequence motifs have been identified in certain antimicrobial peptide subclasses [e.g., cysteine array in mammalian defensins (4)], and prior studies suggested that structural themes may occur within distinct peptide subsets (5,6). Yet comparatively little is known about potentially more comprehensive relationships common to broader classes of antimicrobial peptides.…”

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confidence: 99%

Multidimensional signatures in antimicrobial peptides

Yount

Yeaman

2004

Proc. Natl. Acad. Sci. U.S.A.

347

307

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Conventional analyses distinguish between antimicrobial peptides by differences in amino acid sequence. Yet structural paradigms common to broader classes of these molecules have not been established. The current analyses examined the potential conservation of structural themes in antimicrobial peptides from evolutionarily diverse organisms. Using proteomics, an antimicrobial peptide signature was discovered to integrate stereospecific sequence patterns and a hallmark three-dimensional motif. This striking multidimensional signature is conserved among disulfide-containing antimicrobial peptides spanning biological kingdoms, and it transcends motifs previously limited to defined peptide subclasses. Experimental data validating this model enabled the identification of previously unrecognized antimicrobial activity in peptides of known identity. The multidimensional signature model provides a unifying structural theme in broad classes of antimicrobial peptides, will facilitate discovery of antimicrobial peptides as yet unknown, and offers insights into the evolution of molecular determinants in these and related host defense effector molecules.

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“…The biologic activities of duramycin and its close analog, cinnamycin, have been well characterized, and their PtdEbinding activity was used for in vitro biologic studies (12)(13)(14)(15)(16). Duramycin and cinnamycin have similar PtdE-binding activities, in which the 2 peptides differ by a single amino acid at the distal end away from the binding pocket.…”

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confidence: 99%

^99mTc-Labeled Duramycin as a Novel Phosphatidylethanolamine-Binding Molecular Probe

Zhao¹,

Li²,

Bugenhagen³

2008

J Nucl Med

122

121

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With only 19 amino acids, duramycin is the smallest known polypeptide that has a defined 3-dimensional binding structure. Duramycin binds phosphatidylethanolamine (PtdE) at a 1:1 ratio with high affinity and exclusive specificity. As an abundant binding target, PtdE is a major phospholipid and accounts for about 20% of the phospholipid content in mammalian cellular membranes. PtdE is externalized to the surface of apoptotic cells and also becomes accessible in necrotic cells because of compromised plasma membrane integrity. Given the unique physicochemical properties of duramycin and the availability of PtdE in acute cell death, the goal of this study was to develop and evaluate 99m Tc-duramycin as a novel molecular probe for imaging PtdE. Methods: Duramycin is covalently modified with succinimidyl 6-hydrazinonicotinate acetone hydrazone (HYNIC) and labeled with 99m Tc using a coordination chemistry involving tricine-phosphine coligands. The retention of PtdE-binding activities was confirmed using competition assays with PtdEcontaining liposomes. The blood clearance, pharmacokinetics, and biodistribution of 99m Tc-duramycin were measured in rats. Finally, 99m Tc-duramycin binding to acute cell death in vivo was demonstrated using a rat model of acute myocardial infarction induced by ischemia and reperfusion and confirmed using autoradiography and histology. Results: HYNIC-derivatized duramycin with 1:1 stoicheometry was synthesized and confirmed by mass spectrometry. The radiolabeling efficiency was 80%-85%, radiochemical purity was 78%-89%, and specific activity was 54 GBq. The radiotracer was purified with high-performance liquid chromatography radiodetection before use. The specific uptake of 99m Tc-duramycin in apoptotic cells, compared with that in viable control cells, was enhanced by more than 30-fold. This binding was competitively diminished in the presence of PtdE-containing liposomes but not by liposomes consisting of other phospholipid species. Intravenously injected 99m Tc-duramycin has favorable pharmacokinetic and biodistribution profiles: it quickly clears from the circulation via the renal system, with a blood half-life of less than 4 min in rats. The hepatic and gastrointestinal uptake were very low. 99m Tc-duramycin is completely unmetabolized in vivo, and the intact agent is recovered from the urine. Combined with a fast clearance and low hepatic background, the avid binding of 99m Tc-duramycin to the infarcted myocardium quickly becomes conspicuous shortly after injection. The uptake of radioactivity in infarcted tissues was confirmed by autoradiography and histology. Conclusion: 99m Tc-duramycin is a stable, low-molecular-weight PtdE-binding radiopharmaceutical, with favorable in vivo imaging profiles. It is a strong candidate as a molecular probe for PtdE imaging and warrants further development and characterization.

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Posttranslationally modified bacteriocins—the lantibiotics

Cited by 174 publications

References 88 publications

The cyclization of peptides and depsipeptides

The cyclization of peptides and depsipeptides

Multidimensional signatures in antimicrobial peptides

^99mTc-Labeled Duramycin as a Novel Phosphatidylethanolamine-Binding Molecular Probe

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