# Backbone-modified agonists of B-family GPCRs

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $346,932

## Abstract

SUMMARY
 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 α-amino acid residues with β-amino acid residues, to
generate α/β-peptides. This backbone-modification strategy is distinct from and complementary to
the more traditional approach of modifying α-amino acid side chains. Inserting β residues inhibits
degradation by proteases, which was our original motivation for exploring the backbone-
modification strategy. However, we have recently discovered that αβ 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 α/β-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.

## Key facts

- **NIH application ID:** 9851402
- **Project number:** 5R01GM056414-22
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SAMUEL H. GELLMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,932
- **Award type:** 5
- **Project period:** 1997-09-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851402

## Citation

> US National Institutes of Health, RePORTER application 9851402, Backbone-modified agonists of B-family GPCRs (5R01GM056414-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851402. Licensed CC0.

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