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Dissertation/Thesis Abstract

Innovative use of fatty acid acylation to enhance biological action and biophysical properties of peptide therapeutics
by Ward, Brian P., Ph.D., Indiana University, 2012, 187; 3544924
Abstract (Summary)

Long-chain, saturated fatty acid acylation is a native post-translational chemical modification capable of promoting protein-membrane association that has subsequently been adapted for medicinal purposes to increase the half-life of therapeutic peptides. We explored fatty acylation in complement to peptide sequence optimization in pursuit of glucagon-based peptides that activate multiple structurally-related receptors, including the glucagon and glucagon-like peptide 1 (GLP-1) receptors. The research program aimed to identify novel treatments for diabetes and obesity, and understand the molecular rationales for important pharmacological observations made throughout the process.

This Thesis characterized fatty-acylated glucagon analogs and discovered previously unknown relationships between the chemical structure of the acylation, its site for incorporation and peptide biophysical and pharmacologic properties, which identified potent, long-acting, peptide-based agonists and co-agonists at the glucagon and GLP-1 receptors. Preclinical experiments in collaboration with Professor Tschöp' research group at the University of Cincinnati allowed us to use these peptides for development of a new pharmacological approach to treating obesity.

Observations described herein include that selection of the fatty acylation site in the peptide backbone contributes to water solubility and propensity to self-aggregation, which collectively influence potency of biological action. The chemical nature of the acylation can delay the onset and prolong duration of peptide activity via non-covalent and reversible albumin binding. Structural analysis of acylated glucagon analogs revealed that these acylations inherently stabilize helical structure through energetically-favorable interactions, which impacts pharmacologic function. This structure-function relationship allowed us to gain a broader perspective for the physiological role of fatty acylation in nature.

Our work establishes a family of fatty-acylated glucagon analogs with exciting prospects for treating metabolic disorders including diabetes, obesity, and possibly even neurodegenerative conditions. It also provides new methodology to guide the expansion of medicinal applications of fatty acylation to peptide, protein and potentially other molecules in effort to fight disease.

Indexing (document details)
Advisor: DiMarchi, Richard D.
Commitee: Aron, Zachary A., Bauer, Carl E., Giedroc, David P.
School: Indiana University
Department: Biochemistry and Molecular Biology
School Location: United States -- Indiana
Source: DAI-B 74/04(E), Dissertation Abstracts International
Subjects: Pharmacology, Biochemistry, Medicine
Keywords: Acylation, Diabetes, Fatty acids, Glucagon, Helix, Obesity, Peptides
Publication Number: 3544924
ISBN: 978-1-267-76364-8
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