Insulin-like Growth Factor 1 Analogs Clicked in the C Domain: Chemical Synthesis and Biological Activities
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
MR/K000179/1
Medical Research Council - United Kingdom
- MeSH
- Arginine chemistry MeSH
- NIH 3T3 Cells drug effects MeSH
- Click Chemistry MeSH
- Cycloaddition Reaction MeSH
- Disulfides chemistry MeSH
- Fibroblasts MeSH
- Phosphorylation MeSH
- Insulin-Like Growth Factor I analogs & derivatives chemical synthesis chemistry metabolism pharmacology MeSH
- Humans MeSH
- Copper chemistry MeSH
- Methionine chemistry MeSH
- Mice MeSH
- Drug Evaluation, Preclinical methods MeSH
- Protein Domains MeSH
- Proto-Oncogene Proteins c-akt metabolism MeSH
- Receptor, IGF Type 1 metabolism MeSH
- Solid-Phase Synthesis Techniques MeSH
- Triazoles chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Arginine MeSH
- Disulfides MeSH
- IGF1 protein, human MeSH Browser
- Insulin-Like Growth Factor I MeSH
- Copper MeSH
- Methionine MeSH
- Proto-Oncogene Proteins c-akt MeSH
- Receptor, IGF Type 1 MeSH
- Triazoles MeSH
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.
References provided by Crossref.org
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