Insulin-like Growth Factor 1 Analogs Clicked in the C Domain: Chemical Synthesis and Biological Activities

• Published in: Journal of medicinal chemistry 2017-12, Vol.60 (24), p.10105-10117
• Main Authors: Macháčková, Kateřina, Collinsová, Michaela, Chrudinová, Martina, Selicharová, Irena, Pícha, Jan, Buděšínský, Miloš, Vaněk, Václav, Žáková, Lenka, Brzozowski, Andrzej M, Jiráček, Jiří
• Format: Article
• Language: English
• Subjects: Animals; Arginine - chemistry; Click Chemistry; Copper - chemistry; Cycloaddition Reaction; Disulfides - chemistry; Drug Evaluation, Preclinical - methods; Fibroblasts; Humans; Insulin-Like Growth Factor I - analogs & derivatives; Insulin-Like Growth Factor I - chemical synthesis; Insulin-Like Growth Factor I - chemistry; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - pharmacology; Methionine - chemistry; Mice; NIH 3T3 Cells - drug effects; Phosphorylation; Protein Domains; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - metabolism; Solid-Phase Synthesis Techniques; Triazoles - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01331

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.