Modulation of the antagonistic properties of an insulin mimetic peptide by disulfide bridge modifications

0567614 - ÚOCHB 2024 RIV GB eng J - Článek v odborném periodiku
Lubos, Marta - Pícha, Jan - Selicharová, Irena - Žák, Jiří - Buděšínský, Miloš - Mitrová, Katarína - Žáková, Lenka - Jiráček, Jiří
Modulation of the antagonistic properties of an insulin mimetic peptide by disulfide bridge modifications.
Journal of Peptide Science. Roč. 29, č. 7 (2023), č. článku e3478. ISSN 1075-2617. E-ISSN 1099-1387
Grant CEP: GA MŠMT(CZ) LX22NPO5104; GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: antagonism * dicarba * disulfide mimetics * insulin mimetic peptide * insulin receptor * staple * triazole
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 2.1, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1002/psc.3478

Insulin is a peptide responsible for regulating the metabolic homeostasis of theorganism, it elicits its effects through binding to the transmembrane insulin receptor(IR). Insulin mimetics with agonistic or antagonistic effects toward the receptor arean exciting field of research and could find applications in treating diabetes ormalignant diseases. We prepared five variants of a previously reported 20-amino acidinsulin-mimicking peptide. These peptides differ from each other by the structure ofthe covalent bridge connecting positions 11 and 18. In addition to the peptide with a disulfide bridge, a derivative with a dicarba bridge and three derivatives with a1,2,3-triazole differing from each other by the presence of sulfur or oxygen in theirstaples were prepared. The strongest binding to IR was exhibited by the peptide with a disulfide bridge. All other derivatives only weakly bound to IR, and a relationshipbetween increasing bridge length and lower binding affinity can be inferred. Despite their nanomolar affinities, none of the prepared peptide mimetics was able to activate the insulin receptor even at high concentrations, but all mimetics were able to inhibit insulin-induced receptor activation. However, the receptor remained approximately 30% active even at the highest concentration of the agents, thus, the agents behave as partial antagonists. An interesting observation is that these mimetic peptides do not antagonize insulin action in proportion to their binding affinities. The compounds characterized in this study show that it is possible to modulate the functional properties of insulin receptor peptide ligands using disulfide mimetics.
Trvalý link: https://hdl.handle.net/11104/0338851