Specific Binding of Ro 09-0198 (Cinnamycin) to Phosphatidylethanolamine:  A Thermodynamic Analysis

Machaidze, Gia; Ziegler, and André; Seelig, Joachim

doi:10.1021/bi015841c

Cited by 62 publications

(56 citation statements)

References 26 publications

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“…3). Similar to many detergents and amphipathic peptides, the membrane partitioning of AmB may alternatively be driven primarily by the classic hydrophobic effect (67,68). Moreover, because AmdeB and MeAmdeB both contain the same putatively redox active polyene motif found in AmB and readily bind to LUVs and yeast cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities

Palacios

Dailey

Siebert

et al. 2011

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

118

134

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Amphotericin B is the archetype for small molecules that form transmembrane ion channels. However, despite extensive study for more than five decades, even the most basic features of this channel structure and its contributions to the antifungal activities of this natural product have remained unclear. We herein report that a powerful series of functional group-deficient probes have revealed many key underpinnings of the ion channel and antifungal activities of amphotericin B. Specifically, in stark contrast to two leading models, polar interactions between mycosamine and carboxylic acid appendages on neighboring amphotericin B molecules are not required for ion channel formation, nor are these functional groups required for binding to phospholipid bilayers. Alternatively, consistent with a previously unconfirmed third hypothesis, the mycosamine sugar is strictly required for promoting a direct binding interaction between amphotericin B and ergosterol. The same is true for cholesterol. Synthetically deleting this appendage also completely abolishes ion channel and antifungal activities. All of these results are consistent with the conclusion that a mycosamine-mediated direct binding interaction between amphotericin B and ergosterol is required for both forming ion channels and killing yeast cells. The enhanced understanding of amphotericin B function derived from these synthesis-enabled studies has helped set the stage for the more effective harnessing of the remarkable ion channel-forming capacity of this prototypical small molecule natural product.

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Section: Discussionmentioning

confidence: 99%

Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities

Palacios

Dailey

Siebert

et al. 2011

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

118

134

View full text Add to dashboard Cite

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“…In addition to PE headgroup recognition, hydrophobic interactions with the phospholipid acyl chains are required for efficient membrane targeting (64). Cinnamycin and duramycin possess a binding pocket that fits a PE headgroup, and the binding is stabilized by an ion-pair interaction between the ammonium group of PE and the carboxylate of Asp-15.…”

Section: Importance Of the "Bioactive Patch" And Hydrophobic Propertimentioning

confidence: 99%

Phosphatidylethanolamine Binding Is a Conserved Feature of Cyclotide-Membrane Interactions

Henriques

Huang

Castanho

et al. 2012

Journal of Biological Chemistry

122

208

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Background: Cyclotides are a family of plant-expressed pesticidal cyclic peptides. Results: A broad range of cyclotides specifically interact with membranes containing phosphatidylethanolamine (PE)-phospholipids. Conclusion: Cyclotide bioactivity correlates with an ability to target, insert into, and disrupt lipid membranes containing PE-phospholipids. Significance: Cyclotides constitute a new lipid-binding protein family that has potential as a scaffold to target tumor cells.

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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.…”

mentioning

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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Specific Binding of Ro 09-0198 (Cinnamycin) to Phosphatidylethanolamine: A Thermodynamic Analysis

Cited by 62 publications

References 26 publications

Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities

Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities

Phosphatidylethanolamine Binding Is a Conserved Feature of Cyclotide-Membrane Interactions

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

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