Enhanced disulphide bond stability contributes to the once-weekly profile of insulin icodec.

Autor: Hubálek F; Novo Nordisk A/S, Maaloev, Denmark. FHUB@novonordisk.com., Cramer CN; Novo Nordisk A/S, Maaloev, Denmark., Helleberg H; Novo Nordisk A/S, Maaloev, Denmark., Johansson E; Novo Nordisk A/S, Maaloev, Denmark., Nishimura E; Novo Nordisk A/S, Maaloev, Denmark., Schluckebier G; Novo Nordisk A/S, Maaloev, Denmark., Steensgaard DB; Novo Nordisk A/S, Maaloev, Denmark., Sturis J; Novo Nordisk A/S, Maaloev, Denmark., Kjeldsen TB; Novo Nordisk A/S, Maaloev, Denmark.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 20; Vol. 15 (1), pp. 6124. Date of Electronic Publication: 2024 Jul 20.
DOI: 10.1038/s41467-024-50477-9
Abstrakt: Insulin icodec is a once-weekly insulin analogue that has a long half-life of approximately 7 days, making it suitable for once weekly dosing. The Insulin icodec molecule was developed based on the hypothesis that lowering insulin receptor affinity and introducing a strong albumin-binding moiety would result in a long insulin half-life, provided that non-receptor-mediated clearance is diminished. Here, we report an insulin clearance mechanism, resulting in the splitting of insulin molecules into its A-chain and B-chain by a thiol-disulphide exchange reaction. Even though the substitutions in insulin icodec significantly stabilise insulin against such degradation, some free B-chain is observed in plasma samples from minipigs and people with type 2 diabetes. In summary, we identify thiol-disulphide exchange reactions to be an important insulin clearance mechanism and find that stabilising insulin icodec towards this reaction significantly contributes to its long pharmacokinetic/pharmacodynamic profile.
(© 2024. The Author(s).)
Databáze: MEDLINE
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