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Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off-target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo, possesses an azobenzene photoresponsive element, affording isomer-biased GLP-1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival.

Original publication

DOI

10.1002/anie.201506384

Type

Journal article

Journal

Angew Chem Int Ed Engl

Publication Date

2015

Volume

54

Pages

15565 - 15569

Keywords

Amino Acid Sequence Animals CHO Cells Cell Line, Transformed Cricetinae Cricetulus Diabetes Mellitus, Type 2/drug therapy Glucagon-Like Peptide-1 Receptor/agonists/metabolism Incretins/*chemistry Insulin/*metabolism Insulin Secretion Liraglutide/chemistry/*pharmacology/therapeutic use Mice Molecular Mimicry Molecular Sequence Data Signal Transduction beta cells insulin liraglutide photopharmacology type 2 diabetes