A depot-forming glucagon-like peptide-1 fusion protein reduces blood glucose for five days with a single injection

Abstract

Peptide drugs are an exciting class of pharmaceuticals for the treatment of a variety of diseases; however, their short half-life dictates multiple and frequent injections causing undesirable side-effects. Herein, we describe a novel peptide delivery system that seeks to combine the attractive features of prolonged circulation time with a prolonged release formulation. This system consists of glucagon-like peptide-1, a type-2 diabetes drug fused to a thermally responsive, elastin-like-polypeptide (ELP) that undergoes a soluble-insoluble phase transition between room temperature and body temperature, thereby forming an injectable depot. We synthesized a set of GLP-1-ELP fusions and verified their proteolytic stability and potency in vitro. Significantly, a single injection of depot forming GLP-1-ELP fusions reduced blood glucose levels in mice for up to 5 days, 120 times longer than an injection of the native peptide. These findings demonstrate the unique advantages of using ELPs to release peptide-ELP fusions from a depot combined with enhanced systemic circulation to create a tunable peptide delivery system.

Applications of elastin-like polypeptides in drug delivery

“…Upon slow dissolution of the GLP-1 ELP fusion depot the ELP then provides a long-circulating macromolecular carrier for its peptide drug cargo. Fluorophore-labeled GLP-1 ELP fusion depots were retained at the subcutaneous site of administration in the mouse torso over the course of 5 days, as visualized by near-infrared imaging (Figure 7) [107]. In C57BL/6 J mice this prolonged residence of a single subcutaneous injection of depot forming GLP-1 ELP fusion reduced fed glucose levels approximately 30% for 5 days.…”

Elastin-like polypeptides: Therapeutic applications for an emerging class of nanomedicines

“…More specifically, the 30 amino acid glucagon-like peptide 1 (GLP-1), which possesses a short half-life (<2 min), was chosen as an ELP fusion candidate due to its role in promoting insulin release from pancreatic β-cells[138]. Two 50 kDa (GLP-1)-ELPs were designed with the first property of room temperature solubility and the ability to form a stable, coacervate-based drug depot following subcutaneous injection into C57BL/6J mice; the second fusion served as a control which remained soluble at body temperature.…”

Stromal Cell-Derived Growth Factor-1 Alpha-Elastin Like Peptide Fusion Protein Promotes Cell Migration and Revascularization of Experimental Wounds in Diabetic Mice

“…23 Due to their interesting biological properties, ELPs have been used in several biotechnology and pharmaceutical applications, including targeted delivery of therapeutic drugs 24 and prolonging the half-life of drugs in vivo. 25 The fusion of ELPs to KGF was successfully completed by Koria et al 15 However, the fusion of SDF1 to an ELP for use in chronic wounds is innovative. While this research has focused on chronic wounds, SDF1-ELP could be exploited in other injury types where SDF1 is needed to recruit stem cells to promote local tissue regeneration.…”