Insulin-like Growth Factor 1 Analogs Clicked in the C Domain: Chemical Synthesis and Biological Activities
| Autor: | Miloš Buděšínský, Václav Vaněk, Irena Selicharová, Michaela Collinsová, Lenka Žáková, Jiří Jiráček, Martina Chrudinová, Kateřina Macháčková, Jan Pícha, Andrzej M. Brzozowski |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Stereochemistry medicine.medical_treatment Drug Evaluation Preclinical Triazole Arginine 01 natural sciences Chemical synthesis Receptor IGF Type 1 Mice 03 medical and health sciences Insulin-like growth factor chemistry.chemical_compound Methionine Protein Domains Drug Discovery medicine Animals Humans Disulfides Insulin-Like Growth Factor I Phosphorylation Receptor Solid-Phase Synthesis Techniques chemistry.chemical_classification Cycloaddition Reaction 010405 organic chemistry Growth factor Disulfide bond Fibroblasts Triazoles Combinatorial chemistry Cycloaddition 0104 chemical sciences Amino acid 030104 developmental biology chemistry NIH 3T3 Cells Molecular Medicine Click Chemistry Proto-Oncogene Proteins c-akt Copper |
| Zdroj: | Journal of Medicinal Chemistry. 60:10105-10117 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b01331 |
| Popis: | Human insulin-like growth factor 1 (IGF-1) is a 70 amino acid protein hormone, with key impact on growth, development, and lifespan. The physiological and clinical importance of IGF-1 prompted challenging chemical and biological trials toward the development of its analogs as molecular tools for the IGF-1 receptor (IGF1-R) studies and as new therapeutics. Here, we report a new method for the total chemical synthesis of IGF-1 analogs, which entails the solid-phase synthesis of two IGF-1 precursor chains that is followed by the CuI-catalyzed azide-alkyne cycloaddition ligation and by biomimetic formation of a native pattern of disulfides. The connection of the two IGF-1 precursor chains by the triazole-containing moieties, and variation of its neighboring sequences (Arg36 and Arg37), was tolerated in IGF-1R binding and its activation. These new synthetic IGF-1 analogs are unique examples of disulfide bonds' rich proteins with intra main-chain triazole links. The methodology reported here also presents a convenient synthetic platform for the design and production of new analogs of this important human hormone with non-standard protein modifications. |
| Databáze: | OpenAIRE |
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