Strategy for the synthesis of multivalent peptide-based nonsymmetric dendrimers by native chemical ligation

Dirksen, Anouk; Meijer, E. W.; Adriaens, Wencke; Hackeng, Tilman M.

doi:10.1039/b600286b

Cited by 50 publications

(64 citation statements)

References 8 publications

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“…Another example which combines the use of targeting ligands RGDs and Gd 3+ -DTPA (diethylenetriaminepentaacetic acid) units has been recently developed as MRI contrast agent. This system is based on a polylysine dendrimer prepared via chemical ligation, in which in one dendritic edge it is conjugated to RGDs and the other to MRI contrast agents [219].…”

Section: Dendrimersmentioning

confidence: 99%

Peptide-Based Polymer Therapeutics

2014

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Abstract:Polypeptides are envisaged to achieve a major impact on a number of different relevant areas such as biomedicine and biotechnology. Acquired knowledge and the increasing interest on amino acids, peptides and proteins is establishing a large panel of these biopolymers whose physical, chemical and biological properties are ruled by their controlled sequences and composition. Polymer therapeutics has helped to establish these polypeptide-based constructs as polymeric nanomedicines for different applications, such as disease treatment and diagnostics. Herein, we provide an overview of the advantages of these systems and the main methodologies for their synthesis, highlighting the different polypeptide architectures and the current research towards clinical applications.

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Section: Dendrimersmentioning

confidence: 99%

Peptide-Based Polymer Therapeutics

2014

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“…ESI-MS confirmed a mass decrease of 2, representing the loss of 2 protons from the cystein side chains due to the generation of 1 disulfide bond (S-S). Biotinylated poly(lysine) dendritic wedge, a construct comprising 8 Gddiethylenetriaminepentaacetic acid (DTPA) moieties, was synthesized and purified similarly (21,22).…”

Section: Preparation Of Cngr-labeled Paramagnetic Quantum Dotsmentioning

confidence: 99%

Quantitative Molecular Magnetic Resonance Imaging of Tumor Angiogenesis Using cNGR-Labeled Paramagnetic Quantum Dots

et al. 2008

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The objective of this study was to develop and apply cyclic Asn-Gly-Arg (cNGR)-labeled paramagnetic quantum dots (cNGR-pQDs) for the noninvasive assessment of tumor angiogenic activity using quantitative in vivo molecular magnetic resonance imaging (MRI). cNGR was previously shown to colocalize with CD13, an aminopeptidase that is highly overexpressed on angiogenic tumor endothelium. Because angiogenesis is important for tumor growth and metastatization, its in vivo detection and quantification may allow objective diagnosis of tumor status and evaluation of treatment response. I.v. injection of cNGR-pQDs in tumorbearing mice resulted in increased quantitative contrast, comprising increased longitudinal relaxation rate and decreased proton visibility, in the tumor rim but not in tumor core or muscle tissue. This showed that cNGR-pQDs allow in vivo quantification and accurate localization of angiogenic activity. MRI results were validated using ex vivo two-photon laser scanning microscopy (TPLSM), which showed that cNGR-pQDs were primarily located on the surface of tumor endothelial cells and to a lesser extent in the vessel lumen. In contrast, unlabeled pQDs were not or only sparsely detected with both MRI and TPLSM, supporting a high specificity of cNGR-pQDs for angiogenic tumor vasculature. [Cancer Res 2008;68(18):7676-83]

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“…Starting from a tetravalent, lysinebased dendritic scaffold, four glycine residues were inserted per arm to provide additional spacing before coupling of the cysteine end groups. [14] Ligation of 4 equiv of S-peptide thioester with 1 equiv of lysine wedge resulted in full conversion to the S-peptide tetramer in one hour. The S-peptide tetramer was purified using preparative reversed-phase (RP) HPLC and characterized by mass spectrometry (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…[ Cysteine-functionalized lysine wedge: The cysteine-functionalized lysine wedge was prepared as described by A. Dirksen et al [14] (KETAAAKFERQHMDSSTSAAGG)4-l-lysine dendritic wedge: KETAAAKFERQHA C H T U N G T R E N N U N G (Dnp)MDSSTSAAGG-MPAL (25.4 mg, 9.6 mmol) was dissolved in Tris buffer (3 mL, 70 mm, pH 8.0) containing 6 m guanidine and the l-lysine dendritic wedge (4.1 mg, 2.4 mmol) was added. Thiophenol (1 % v/v) and benzyl mercaptan (1 % v/v) were added and the pH was checked (7.5).…”

Section: Ketaaakferqhmdsstsaaggmentioning

confidence: 99%

Noncovalent Synthesis of Protein Dendrimers

Lempens

Baal

Dongen

et al. 2009

Chemistry A European J

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The covalent synthesis of complex biomolecular systems such as multivalent protein dendrimers often proceeds with low efficiency, thereby making alternative strategies based on noncovalent chemistry of high interest. Here, the synthesis of protein dendrimers using a strong but noncovalent interaction between a peptide and complementary protein is proposed as an efficient strategy to arrive at dendrimers fully functionalized with protein domains. The association of S-peptide to S-protein results in the formation of an active enzyme (ribonuclease S) and therefore serves as an ideal system to explore this synthetic approach. Native chemical ligation was used to couple four S-peptides by means of their C-terminal thioester to a cysteine-functionalized dendritic scaffold, thus yielding a tetravalent S-peptide wedge. A fully functional ribonuclease S tetramer was prepared by addition of four equivalents of S-protein. Biophysical techniques (isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), and mass spectrometry) and an enzymatic activity assay were used to verify the formation of the multivalent complex. The noncovalent synthetic strategy presented here provides access to well-defined, dynamic, semisynthetic protein assemblies in high yield and is therefore of interest to the field of nanomedicine as well as biomaterials.

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Strategy for the synthesis of multivalent peptide-based nonsymmetric dendrimers by native chemical ligation

Abstract: A strategy for the synthesis of multivalent peptide-based nonsymmetric dendrimers by native chemical ligation using poly(lysine) dendritic wedges as scaffolds is presented.

Cited by 50 publications

References 8 publications

Peptide-Based Polymer Therapeutics

Peptide-Based Polymer Therapeutics

Quantitative Molecular Magnetic Resonance Imaging of Tumor Angiogenesis Using cNGR-Labeled Paramagnetic Quantum Dots

Noncovalent Synthesis of Protein Dendrimers

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