Macháčková, Kateřina, Collinsová, Michaela, Chrudinová, Martina et al. (7 more authors) (2017) Insulin-like Growth Factor 1 Analogs Clicked in the C Domain:Chemical Synthesis and Biological Activities. JOURNAL OF MEDICINAL CHEMISTRY. pp. 10105-10117. ISSN 0022-2623
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 American Chemical Society. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 16 May 2018 14:00 |
Last Modified: | 16 Oct 2024 14:44 |
Published Version: | https://doi.org/10.1021/acs.jmedchem.7b01331 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1021/acs.jmedchem.7b01331 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:130986 |