![]() Over the past decades, a number of small-sized proteins and peptides, such as cytokines and hormones, have been developed and clinically used as therapeutic agents for various diseases, ,, ]. The present approach can be effectively used in enhancing the efficacy of small-sized therapeutic proteins and peptides through an enhanced blood circulation time. The utility and potential of our approach was demonstrated by the efficient control of the blood glucose level in type-2 diabetes mouse models using the HSA-specific protein binder-fused GLP-1 over a prolonged time period. The fused GLP-1 was shown to have a significantly improved pharmacokinetic property: The terminal half-life of the fused GLP-1 increased to approximately 10 h, and the area under the curve was 5-times higher than that of the control. As a proof-of-concept, the protein binder composed of LRR (Leucine-rich repeat) modules was genetically fused to the N-terminus of Glucagon-like Peptide-1 (GLP-1). Here we present the development of a human serum albumin (HSA)-specific protein binder with a binding affinity of 4.3 nM through a phage display selection and modular evolution approach to extend the blood half-life of a small-sized therapeutic protein. However, their short half-life in blood owing to fast renal clearance usually results in a low therapeutic efficacy and frequent dosing. Many small-sized proteins and peptides, such as cytokines and hormones, are clinically used for the treatment of a variety of diseases.
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