8RRP

Insulin Icodec - A14E B16H B25H B29Ne-C20 diacid-LgGlu-2xAdo desB30 human insulin

Summary for 8RRP

• Entry DOI: 10.2210/pdb8rrp/pdb
• Descriptor: Insulin, Insulin B chain, ACETATE ION, ... (4 entities in total)
• Functional Keywords: insulin, hormone
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 17063.39

Authors

Schluckebier, G.,Johansson, E. (deposition date: 2024-01-23, release date: 2024-07-10, Last modification date: 2024-11-13)

Primary citation

Hubalek, F.,Cramer, C.N.,Helleberg, H.,Johansson, E.,Nishimura, E.,Schluckebier, G.,Steensgaard, D.B.,Sturis, J.,Kjeldsen, T.B.
Enhanced disulphide bond stability contributes to the once-weekly profile of insulin icodec.
Nat Commun, 15:6124-6124, 2024

PubMed Abstract: 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.

PubMed: 39033137
DOI: 10.1038/s41467-024-50477-9

Experimental method

X-RAY DIFFRACTION (2 Å)