Recombinant Insulin-Like Growth Factor 1 Dimers: Receptor Binding Affinities and Activation Abilities

0570637 - ÚOCHB 2024 RIV US eng J - Článek v odborném periodiku
Lin, Jingjing - Asai, Seiya - Selicharová, Irena - Mitrová, Katarína - Kaminský, Jakub - Young, E. - Jiráček, Jiří
Recombinant Insulin-Like Growth Factor 1 Dimers: Receptor Binding Affinities and Activation Abilities.
International Journal of Peptide Research and Therapeutics. Roč. 29, č. 2 (2023), č. článku 33. ISSN 1573-3149. E-ISSN 1573-3904
Grant CEP: GA MŠMT(CZ) LX22NPO5104; GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: IGF-1 * receptor * dimer * insulin * binding * phosphorylation * hormone * folding * agonism * antagonism
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 2.5, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1007/s10989-023-10499-1

Insulin-like growth factor 1 (IGF-1) and its IGF-1 receptor (IGF-1R) belong to an important biological system that is involved in the regulation of normal growth, but that has also been recognized as playing a role in cancer. IGF-1R antagonists could be interesting for the testing of their potential antiproliferative properties as an alternative to IGF-1R tyrosine-kinase inhibitors or anti-IGF-1R monoclonal antibodies. In this study, we were inspired by the successful development of insulin dimers capable of antagonizing insulin effects on the insulin receptor (IR) by simultaneous binding to two separated binding sites and by blocking structural rearrangement of the IR. We designed and produced in Escherichia coli three different IGF-1 dimers in which IGF-1 monomers are interlinked through their N-and C-termini, with linkers having 8, 15 or 25 amino acids. We found that the recombinant products were susceptible to the formation of misfolded or reduced variants, but that some of them were able to bind IGF-1R in low nanomolar affinities and all of them activate IGF-1R proportionally to their binding affinities. Overall, our work can be considered as a pilot study that, although it did not lead to the discovery of new IGF-1R antagonists, explored the possibility of recombinant production of IGF-1 dimers and led to the preparation of active compounds. This work could inspire further studies dealing, for example, with the preparation of IGF-1 conjugates with specific proteins for the study of the hormone and its receptor or for therapeutic applications.
Trvalý link: https://hdl.handle.net/11104/0341946