title: Peptide lipidation stabilizes structure to enhance biological function.
abstract: Medicines that decrease body weight and restore nutrient tolerance could improve human diabetes and obesity treatment outcomes. We developed lipid-acylated glucagon analogs that are co-agonists for the glucagon and glucagon-like peptide 1 receptors, and stimulate weight loss and plasma glucose lowering in pre-diabetic obese mice. Our studies identified lipid acylation (lipidation) can increase and balance in vitro potencies of select glucagon analogs for the two aforementioned receptors in a lipidation site-dependent manner. A general capacity for lipidation to enhance the secondary structure of glucagon analogs was recognized, and the energetics of this effect quantified. The molecular structure of a lipid-acylated glucagon analog in water was also characterized. These results support that lipidation can modify biological activity through thermodynamically-favorable intramolecular interactions which stabilize structure. This establishes use of lipidation to achieve specific pharmacology and implicates similar endogenous post-translational modifications as physiological tools capable of refining biological action in means previously underappreciated.
authors: Department of Chemistry, Indiana University, Bloomington, IN, USA.
authors: Brian P
authors: BP
authors: Ward
authors: Nickki L
authors: NL
authors: Ottaway
authors: Diego
authors: D
authors: Perez-Tilve
authors: Dejian
authors: D
authors: Ma
authors: Vasily M
authors: VM
authors: Gelfanov
authors: Matthias H
authors: MH
authors: Tschöp
authors: Richard D
authors: RD
authors: Dimarchi
keywords: Diabetes; Glucagon; Glucagon Aib2,16 amide, Aib2,16a; Lipid; Obesity; Peptide; Structure