# Novel Agonists and Inverse Agonists for B-Family GPCRs

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $357,321

## Abstract

SUMMARY
 The proposed research focuses on a subset of G protein-coupled receptors (GPCRs) that are
naturally modulated by long polypeptide hormones (family B GPCRs). These receptors control many
important metabolic functions. For example, glucagon-like peptide-1 (GLP-1) activation of the cognate
GPCR, the GLP-1R, helps to control glucose levels in the bloodstream. Synthetic analogues of GLP-1,
including liraglutide and semaglutide (each > 30 residues), are used to treat type 2 diabetes. Parathyroid
hormone (PTH) activates the parathyroid hormone receptor 1 (PTHR1) and thereby helps to control
calcium and phosphate levels in the bloodstream. Agonists of the PTHR1, teriparatide and abaloparatide
(each 34 residues), are used to treat osteoporosis.
 A major focus of the proposed studies is to elucidate how the information encoded in polypeptide
hormones is "read out" by B family GPCRs and transmitted to intracellular partner proteins. This question
is of great interest in terms of basic understanding of signal transduction at the molecular level. Insights
that emerge from the proposed research could support the development of new agonists with tailored
signaling properties and thereby illuminate a path to new therapeutic agents with minimized side effects.
 Recent discoveries have led us to formulate a new hypothesis regarding the bioactive forms of the
natural GLP-1R agonists, GLP-1(7-36) and exendin-4 (Ex-4), in complex with the GLP-1R, and to extend
this hypothesis to other hormone-activated GPCRs (Aims 1 and 2). We propose that retention of a specific
mode of agonist mobility is essential for activity. Although it is widely understood that GPCRs are mobile
proteins, and that agonists transmit information via binding to GPCRs by inducing specific receptor
conformations, which are recognized by cytosolic partner proteins, our hypothesis constitutes a new
perspective. The current view is that the bioactive form of a peptide agonist comprises a single, specific
conformation, while our hypothesis includes specific dynamic modes to define the agonist bioactive form.
The distinction between these two hypotheses is significant because they make different predictions with
regard to designing new agonists. Our hypothesis highlights the need to maintain specific modes of
agonist flexibility, while the traditional view emphasizes rigidification. Therefore, the experimental program
we propose could lead to highly impactful outcomes.
 Aim 3 builds on capabilities established during prior years of support via R01 GM056414, involving
replacement of selected α-amino acid residues with β-amino acid residues. We will try to develop potent
and protease-resistant inverse agonists of constitutively active natural variants of the PTHR1 that are
associated with Jansen's Metaphyseal Chondrodysplasia, for which there is no current therapy.

## Key facts

- **NIH application ID:** 10363423
- **Project number:** 2R01GM056414-24
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SAMUEL H. GELLMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $357,321
- **Award type:** 2
- **Project period:** 1997-09-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363423

## Citation

> US National Institutes of Health, RePORTER application 10363423, Novel Agonists and Inverse Agonists for B-Family GPCRs (2R01GM056414-24). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10363423. Licensed CC0.

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