Journal
MOLECULAR METABOLISM
Volume 2, Issue 4, Pages 468-479Publisher
ELSEVIER
DOI: 10.1016/j.molmet.2013.08.008
Keywords
Glucagon; Lipid; Diabetes; Obesity; Peptide; Structure
Categories
Funding
- Marcadia Biotech
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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. (C) 2013 The Authors. Published by Elsevier GmbH. All rights reserved.
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