Peptide lipidation stabilizes structure to enhance biological function

Brian P. Ward, Nickki L. Ottaway, Diego Perez-Tilve, Dejian Ma, Vasily M. Gelfanov, Matthias H. Tschöp, Richard D. DiMarchi

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

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.

Original languageEnglish
Pages (from-to)468-479
Number of pages12
JournalMolecular Metabolism
Volume2
Issue number4
DOIs
StatePublished - Nov 2013

Keywords

  • Diabetes
  • Glucagon
  • Lipid
  • Obesity
  • Peptide
  • Structure

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