Synthesis and characterization of a high-affinity {alpha}v{beta}6-specific ligand for in vitro and in vivo applications
| Autor: | Ying Horng Liu, Michael J. McGuire, Tsukasa Oyama, Mai Lin, Shunzi Li, Xiankai Sun, Kathlynn C. Brown |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Integrins Convergent synthesis Peptide Antineoplastic Agents Plasma protein binding Mice SCID Biology Ligands Protein Engineering Article Mice Drug Stability Antigens Neoplasm Peptide Library Cell Line Tumor Animals Humans Tissue Distribution Binding site Peptide library chemistry.chemical_classification Binding Sites Protein engineering Ligand (biochemistry) Molecular biology Xenograft Model Antitumor Assays Oncology chemistry Biochemistry Radiopharmaceuticals Peptides Binding domain Protein Binding |
| Zdroj: | Molecular cancer therapeutics. 8(5) |
| ISSN: | 1538-8514 |
| Popis: | The αvβ6 integrin is an attractive therapeutic target for several cancers due to its role in metastasis and its negligible expression in normal tissues. We previously identified a peptide from a phage-displayed peptide library that binds specifically to αvβ6. The tetrameric version of the peptide has higher affinity for its cellular targets than the corresponding monomers. However, the inefficient synthesis limits its clinical potential. We report here a convergent synthesis producing the tetrameric peptide in high yield and purity. The ease of the synthesis allows for rapid optimization of the peptide. We have optimized this αvβ6 integrin–binding peptide, determining the minimal binding domain and valency. Importantly, the half-maximal binding affinity of the optimal peptide for its target cell is in the 40 to 60 pmol/L range, rivaling the affinity of commonly used antibody-targeting reagents. This peptide mediates cell-specific uptake, is functional in diagnostic formats, is stable in sera, and can home to a tumor in an animal. We anticipate that this high-affinity ligand for αvβ6 will find clinical use as a diagnostic and therapeutic reagent. [Mol Cancer Ther 2009;8(5):1239–49] |
| Databáze: | OpenAIRE |
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