A Ferritin-displayed GLP-1 with improved pharmacological activities and pharmacokinetics.

Glucagon-like peptide-1 (GLP-1) is one of incretins (metabolic hormones that stimulate a decrease in blood glucose levels), holding great potential for the treatment of type 2 diabetes mellitus (T2DM). However, the extremely short half-life of 1-2 min hampers the direct application in the clinic. Here, we describe the application of heavy chain of human ferritin (HFt) nanocage as a carrier to improve the pharmacological properties of GLP-1. The GLP-HFt was designed by genetic fusion of GLP-1 to the N-terminus of HFt, and was expressed in inclusion bodies in E. coli. The refolding process was developed to obtain a soluble GLP-HFt protein. The biophysical properties determined by size-exclusion chromatography (SEC), dynamic light scattering (DLS), circular dichroism (CD), transmission electron microscopy (TEM) and x-ray crystallography verified that the GLP-HFt successfully formed a 24-mer nanocage with GLP-1 displayed on the external surface of HFt. The in vivo pharmacokinetics results demonstrated that the GLP-HFt nanocage retained the bioactivity of natural GLP-1, and significantly reduced the blood glucose levels for at least 24 h in a dose-dependent manner and inhibited the food intake for at least 8-10 h. The half-life of GLP-HFt nanocage was approximately 52 h in mice after subcutaneous injection. The prolonged half-life and sustained control of blood glucose levels indicate that GLP-HFt nanocage can be further developed for the treatment of T2DM. Meanwhile, the HFt nanocage proves its great potential as a universal carrier that improves the pharmacodynamic and pharmacokinetic properties of a wide range of therapeutic peptides and proteins.