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

Long-acting insulins are part of the WHO’s List of Essential Medicines, which highlights their importance in the treatment of diabetes. Often their mode of action relies on albumin binding propensity which they owe to chemical conjugations with fatty acids. In this work, we propose an alternative development strategy for albumin-binding insulins through metallacarborane conjugation. In this study, insulin was modified with newly synthesised aldehyde-bearing metallacarboranes through reductive aminations to yield insulin-metallacarborane conjugates (INS-MC). In the conducted assays, INS-MC displayed superior albumin binding capability compared with the currently marketed detemir and degludec (10-fold increase). Strong albumin binding was associated with unchanged biological properties in vitro. This paper provides evidence of a new potential technology in which metallacarboranes can serve as an alternative for fatty acid conjugation in therapeutics where albumin binding is desired.