A New Protractor Potentiates Glucagon-Like Peptide 1 with Slow-Release Depot and Long-Term Action

Abstract

Bioactive peptides display a number of favorable features as therapeutics, but their usage is challenging due to the low metabolic stability and rapid renal clearance. The small-molecule protractor, which functions by the noncovalent binding with serum albumin and protection against systemic clearance, is an attractive tool to elongate peptides’ half-life. Herein, we investigated coomassie brilliant blue (CBB) as a new protractor for the half-life extension of clinically relevant glucagon-like peptide 1 (GLP-1). A series of GLP-1 analogues differentiating with CBB linkers and acylation positions are described. One particularly interesting analogue (coomatide 13) exhibits sub-picomolar potency in vitro and long-term control of glucose homeostasis in mice. A protraction mechanism study reveals that CBB has a high affinity to albumin and pan-interaction with other matrix proteins, enabling to protract peptides in both systemic circulation and the subcutaneous depot. Our study demonstrates that the specific affinity to albumin is not a prerequisite for peptide protraction, and pan-binders might be advantageous.