An Alternative Strategy for Albumin Binding in Therapeutics. Proof-of-Concept Synthesis of Metallacarborane−Insulin Conjugates

Abstract

Abstract Commercialized designs of long-acting insulins often base their protracted mode of action on fatty acid acylation, which enables interaction between insulin and serum albumin. Building on that experience, we propose an alternative design where fatty acids are replaced with self-assembling, highly albumin-affine metallacarboranes. Herein, a series of KB29-modified insulin−metallacarborane conjugates (INS−MCs) was synthesized through conjugations with specially designed aldehyde-bearing metallacarboranes. Owing to metallacarborane modification, INS−MCs noted over 10-fold stronger albumin binding than commercialized insulin detemir and degludec. What is more, conjugation also induced superstructure formation, which was a key feature in the protracted mode of action of insulin degludec. Metallacarborane modification led to suppression of aggregation at elevated temperatures and faster β-amyloid formation under thermomechanical stress. Lastly, the performed conjugations did not induce cytotoxicity, nor did they affect INS−MCs functionality in vitro. The research presented here solidifies a role of metallacarborane in bioconjugation, presenting itself as a viable alternative to fatty acid acylation.

The authors' abstract, as published at the source. Bioconjugate Chemistry, 2026 · DOI ↗