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

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.