A Disulfide‐Constrained Miniprotein with Striking Tumor‐Binding Specificity Developed by Ribosome Display

Zoller, Frederic; Markert, Annette; Barthe, Philippe; Hebling, Ulrike; Altmann, Annette; Lindner, Thomas; Mier, Walter; Haberkorn, Uwe

doi:10.1002/ange.201304603

Cited by 6 publications

(6 citation statements)

References 29 publications

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“…Peptide cyclization is increasingly used in designing bioactive compounds . Cyclization of a peptide apparently restricts its conformational flexibility, resulting in the generation of a peptide that has high affinity to the target molecule.…”

Section: Resultsmentioning

confidence: 99%

Complementary DNA display selection of high-affinity peptides binding the vacuolating toxin (VacA) ofHelicobacter pylori

et al. 2015

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Artificial peptides designed for molecular recognition of a bacterial toxin have been developed. Vacuolating cytotoxin A protein (VacA) is a major virulence factor of Helicobacter pylori, a gram-negative microaerophilic bacterium inhabiting the upper gastrointestinal tract, particularly the stomach. This study attempted to identify specific peptide sequences with high affinity for VacA using systematic directed evolution in vitro, a cDNA display method. A surface plasmon resonance-based biosensor and fluorescence correlation spectroscopy to examine binding of peptides with VacA identified a peptide (GRVNQRL) with high affinity. Cyclization of the peptide by attaching cysteine residues to both termini improved its binding affinity to VacA, with a dissociation constant (Kd ) of 58 nm. This study describes a new strategy for the development of artificial functional peptides, which are promising materials in biochemical analyses and medical applications.

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Section: Resultsmentioning

confidence: 99%

Complementary DNA display selection of high-affinity peptides binding the vacuolating toxin (VacA) ofHelicobacter pylori

et al. 2015

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“…This approach has been used in various applications, such as in the mapping and mimicking of epitopes, the identification of new receptors and natural ligands, high-affinity antibodies and analogs, the isolation of specific antigens binding to bioactive compounds, the production of novel enzyme inhibitors and DNA-binding proteins, and the probing of cellular and tissue-specific processes. Phage display has been successfully applied for the identification of peptides with a high specificity for target tumor neovasculature or a variety of human tumor cells (16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

Section: Biotechnology Methods For Identification Of New Ligands: Dismentioning

confidence: 99%

“…When libraries based on the trypsin inhibitors sunflower trypsin inhibitor and Min23 were applied, peptides were identified by phage display as well as ribosome display for Dll4 and a v b 6 -integrin (31)(32)(33). The Dll4 peptides showed a high affinity, in the range of 4-40 nM, and a serum stability of up to 10 d. When a membrane proteome of HNO97 tumor cells (head and neck squamous cell carcinoma) fractionated by the ProteomeLab PF2D system (Beckman Coulter) and corresponding HNO97 cells for phage display with a sunflower trypsin inhibitor library were used, a novel a v b 6 -integrin-binding peptide (SFITGv6) with stability over a period of 24 h, a high affinity (diffusion constant, 14.8 nM) for a v b 6 -integrin, and an internalization ratio of 37.5% was identified (33).…”

Section: Affinity and Stability Or Scylla And Charybdis: Is There A Smentioning

confidence: 99%

Identification of Ligands and Translation to Clinical Applications

et al. 2017

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Technologic advances in molecular biology and biotechnology are increasingly being used for the development of new tumor-targeting tracers. In oncology, major progress has recently been achieved with peptidic and proteinaceous compounds. The development of new biocompatible molecules relies on the identification and validation of new target structures in close conjunction with the application of novel techniques. The identification of lead compounds by these techniques is followed by the screening of various derivatives of these molecules. Hence, high-throughput methods that generate vast libraries of epitopes have been applied. These libraries are screened to identify the few variants that bind with a high affinity to the target structure. A key feature of this strategy is the large number of candidate molecules that can be identified. Further evaluation and optimization of these molecules requires characterization of structure-function relationships and subsequent improvement with respect to binding, internalization, and biodistribution through a rational design of corresponding analogs.

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“…Identification of high-affinity binders is usually obtained after three to six rounds [28]. Figure 4 shows visualization of a neuroendocrine tumor in a rat model with an iodine-labeled peptide directed against Dll4 which was identified by ribosome display [26].…”

Section: Display Systemsmentioning

confidence: 99%

“…Phage display has successfully been applied for the identification of novel peptides with high specificity for target proteins overexpressed in the tumor neovasculature, such as delta-like ligand 4 (Dll4), or for human lung carcinoma, mammary carcinoma, prostate carcinoma and neuroblastoma cells [1,2,[21][22][23][24][25][26].…”

Section: Display Systemsmentioning

confidence: 99%

Mechanistic and high-throughput approaches for the design of molecular imaging probes and targeted therapeutics

Haberkorn

Mier

Dimitrakopoulou-Strauß

et al. 2014

Clin Transl Imaging

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Recent advances in molecular biology and biotechnology have opened the way for the development of new imaging and treatment modalities based on the biological properties of tissues. In oncology, the major advances have been achieved using peptide and antibody targeting molecules. This approach is based on: (1) the identification of new target structures, and (2) the application of new techniques for the development of new biocompatible molecules. These techniques rely on the identification of lead compounds followed by the screening of various derivatives of these compounds. For this purpose, high-throughput methods have been applied that generate a vast library of possible binders which can be used to screen the whole population for the few variants that show the property of interest. An attractive feature of this strategy is the huge number of candidate molecules that can be used for further evaluation, which consists of the characterization of structure-function relationships and the further improvement by rational design of corresponding analogs.

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A Disulfide‐Constrained Miniprotein with Striking Tumor‐Binding Specificity Developed by Ribosome Display

Abstract: Fold me to hold me: A specific binding agent against the delta‐like ligand 4 protein, which is expressed in angiogenesis, was identified by ribosome display. Specific tumor binding of this molecular imaging agent depends on the appropriate disulfide connectivity of its scaffold.

Cited by 6 publications

References 29 publications

Complementary DNA display selection of high-affinity peptides binding the vacuolating toxin (VacA) ofHelicobacter pylori

Complementary DNA display selection of high-affinity peptides binding the vacuolating toxin (VacA) ofHelicobacter pylori

Identification of Ligands and Translation to Clinical Applications

Mechanistic and high-throughput approaches for the design of molecular imaging probes and targeted therapeutics

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