Elsevier

Molecular Metabolism

Volume 2, Issue 4, November 2013, Pages 468-479
Molecular Metabolism

Original article
Peptide lipidation stabilizes structure to enhance biological function

https://doi.org/10.1016/j.molmet.2013.08.008Get rights and content
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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.

Abbreviations

Glucagon Aib2,16 amide
Aib2,16a

Keywords

Glucagon
Lipid
Diabetes
Obesity
Peptide
Structure

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