Insulin prodrugs with programmed chemical release of an intramolecular cross-link

Abstract Basal insulin therapy is conventionally achieved by one of two broad medicinal approaches that entail protracted absorption at an injection site, or through chemical modification that reduces systemic clearance. We report an alternative approach that employs novel insulin prodrug chemistry to slow the onset of glucose lowering in a controlled manner. 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 at varying speed to a corresponding diketopiperazines (DKP) to initiate the transition from a constrained insulin to a flexible conformation characteristic of bioactive insulin. 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.