The proposed research focuses on synthesis and analysis of a new type of agonist for B- family G protein-coupled receptors (GPCRs). This GPCR family collectively controls many important aspects of physiology. The natural agonists of B-family GPCRs are long polypeptide hormones (>27 residues); efforts to develop small-molecule agonists have been almost entirely unsuccessful for these receptors. Peptides that activate specific B-family GPCRs are used medicinally, including exenatide (39 residues), lixisenatide (45 residues) and liraglutide (30 residues) to treat type 2 diabetes, and teriparatide (34 residues) to treat osteoporosis. The type 2 diabetes drugs are agonists of the glucagon-like peptide-1 receptor (GLP-1R), and the osteoporosis drug is an agonist of the parathyroid hormone receptor 1 (PTHR1). We generate novel agonists by starting from a known agonist peptide, such as GLP-1(7-37) or PTH(1-34), and replacing a subset of the ?-amino acid residues with ?-amino acid residues, to generate ?/?-peptides. This backbone-modification strategy is distinct from and complementary to the more traditional approach of modifying ?-amino acid side chains. Inserting ? residues inhibits degradation by proteases, which was our original motivation for exploring the backbone- modification strategy. However, we have recently discovered that ??? replacement can alter the message conveyed by the peptide to its receptor, that is, this approach can generate biased agonists of the GPCR. Understanding and harnessing this feature of ?/?-peptide agonists is a major focus of the proposed research. Biased agonists are of great biomedical interest because they can be powerful tools for elucidating receptor function and the physiological outcomes of specific signaling pathways. In addition, biased agonists are attractive as drug candidates because they might minimize deleterious side-effects of receptor activation. The proposed research should advance our fundamental understanding of two important signaling networks, provide experimental design strategies that can be applied to other B-family GPCRs of medical interest, and perhaps lay a foundation for the development of a new type of therapeutic agent.

Public Health Relevance

The proposed research focuses on novel molecules that are intended to send biomedically important signals to living cells. These molecules engage receptor proteins located on the external surfaces of cells. Such receptors control many important aspects of physiology, including levels of glucose, calcium and phosphate in the bloodstream, and the function of specific cell types, such as pancreatic ?-cells (which produce insulin) and osteoblasts (which lay down new bone). Peptides that activate specific members of the target receptor class have been developed as drugs, including exenatide, lixisenatide and liraglutide, which are used to treat type 2 diabetes, and teriparatide, which is used to treat osteoporosis. Our research might ultimately lay a foundation for new treatments of these and other human diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Schools of Arts and Sciences
United States
Zip Code
Eddinger, Geoffrey A; Gellman, Samuel H (2018) Differential Effects of ?3 - versus ?2 -Amino Acid Residues on the Helicity and Recognition Properties of Bim BH3-Derived ?/?-Peptides. Angew Chem Int Ed Engl 57:13829-13832
Hager, Marlies V; Clydesdale, Lachlan; Gellman, Samuel H et al. (2017) Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1. Biochem Pharmacol 136:99-108
Checco, James W; Gellman, Samuel H (2017) Iterative Nonproteinogenic Residue Incorporation Yields ?/?-Peptides with a Helix-Loop-Helix Tertiary Structure and High Affinity for VEGF. Chembiochem 18:291-299
Cheloha, Ross W; Chen, Bingming; Kumar, Niyanta N et al. (2017) Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad ? Residue Distribution. J Med Chem 60:8816-8833
Checco, James W; Gellman, Samuel H (2016) Targeting recognition surfaces on natural proteins with peptidic foldamers. Curr Opin Struct Biol 39:96-105
Hager, Marlies V; Johnson, Lisa M; Wootten, Denise et al. (2016) ?-Arrestin-Biased Agonists of the GLP-1 Receptor from ?-Amino Acid Residue Incorporation into GLP-1 Analogues. J Am Chem Soc 138:14970-14979
Cheloha, Ross W; Watanabe, Tomoyuki; Dean, Thomas et al. (2016) Backbone Modification of a Parathyroid Hormone Receptor-1 Antagonist/Inverse Agonist. ACS Chem Biol 11:2752-2762
Cheloha, Ross W; Gellman, Samuel H; Vilardaga, Jean-Pierre et al. (2015) PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol 11:712-24
Checco, James W; Lee, Erinna F; Evangelista, Marco et al. (2015) ?/?-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells. J Am Chem Soc 137:11365-75
Peterson-Kaufman, Kimberly J; Haase, Holly S; Boersma, Melissa D et al. (2015) Residue-Based Preorganization of BH3-Derived ?/?-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in ?-Helix Mimics. ACS Chem Biol 10:1667-75

Showing the most recent 10 out of 75 publications