Insulin Prodrugs with Programmed Chemical Release of an Intramolecular Cross-Link

Purpose Basal insulin therapy is conventionally achieved by one of two broad medicinal approaches that entail either protracted absorption at an injection site or chemical modification which slows systemic clearance. We investigate an alternative approach that employs novel insulin prodrug chemistry to slow the onset of glucose lowering in a controlled manner. Results Reversible attenuation of insulin action is achieved through a series of chemical linkers that structurally constrain the hormone until the point of their programmed chemical degradation. Under physiological conditions, dipeptide-based linkers convert to the corresponding diketopiperazines (DKP) to initiate the transition from a constrained insulin to a flexible conformation characteristic of bioactive insulin with half-lives ranging from 40 to 90 h. Optimization of crosslinking sites allow greater than 50-fold reduction in activity for the closed-form insulin analogue. Conclusion The crosslinking prodrug approach was utilized in the design of insulin structures capable of transition from an inactive to an active conformation, and compatible with once-weekly release profile. The experimental findings establish a path toward improved insulin-mediated glycaemic control through enhanced precision in time of action and compatible with conventional approaches to extend time action, or other therapeutic purposes. Graphical Abstract Insulin prodrug achieved through a constrained macrocyclic conformation with controllable onset of action under physiological conditions.