# Allosteric modulation of beta2- adrenoceptors in the treatment of asthma

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $594,516

## Abstract

PROJECT SUMMARY:
 Beta 2 adrenergic receptor (AR) agonists (-agonists) are prominent prophylaxis and rescue medicines in
asthma. However, the therapeutic efficacy of -agonists is limited by multiple clinical problems associated with
the chronic use of -agonists, including tachyphylaxis and worsening asthma symptoms. Therefore, there is a clinical
need to develop strategies to improve the efficacy of β-agonists. At a molecular level, β2AR binds to multiple proteins such
as Gs, -arrestins, G-protein receptor kinase, and protein kinase A, leading to intricate, multidimensional signaling and
functional effects. The canonical β2AR-Gs signaling relaxes airway smooth muscle (ASM), whereas β2AR-arrestin
signaling promotes receptor desensitization, cell proliferation, and mucus production in the airways. Leveraging the
concepts of “Biased agonism” and “Allosteric modulation” in G protein-coupled receptor pharmacology, in this application,
we propose to employ advanced computational approaches and identify novel β2AR conformations and allosteric sites,
and develop ligands that bind to those sites and promote specific (beneficial) signaling and functional effect in airways. Our
studies identified unique -agonist-induced conformations and a novel allosteric site on the β2AR. Database screening
identified small-molecule ligands that can bind to this site and modulate β2AR-Gs signaling and relaxation of human ASM
cells and bronchodilation of human and murine airways. Motivated by these data, we hypothesize that selective
enhancement of the β2AR-Gs signaling by positive allosteric modulators (AMs) of β2AR developed by
computational approaches will provide therapeutic benefits in asthma. In Aim 1, we will employ advanced
computational approaches, including atomistic molecular dynamics simulations at a superior spatial and
temporal resolution in the presence of interacting proteins and different clinically relevant -agonists. Further, we
will develop functional group affinity patterns, FragMaps, for different conformations of β2AR and identify allosteric
binding sites and screen for ligands binding to those sites. These studies will also establish the structural basis
for the modulation of specific signaling of β2AR by the AMs. Aim 2 studies will elucidate the signaling (Gs: Gs
activation, cyclic AMP generation, protein kinase A activation; -arrestin: arrestin recruitment, phosphorylation of
p42/p44, loss of cell surface expression of β2AR) mechanisms and functional effects (ASM relaxation,
bronchodilation, ASM cell proliferation, and mucus/cytokine secretion by human airway epithelial cells) of -
agonists modulated by AMs using HEK293 cells expressing human β2AR and human ASM/airway epithelial cells,
murine and human lung slices, and transgenic mice expressing human β2AR in smooth muscle. Previous studies have
demonstrated that -agonists promote asthma pathology in a β2AR-arrestin-dependent manner in murine models.
Enhancing canonical β2AR-Gs signali...

## Key facts

- **NIH application ID:** 10856405
- **Project number:** 1R01HL173113-01
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Deepak A Deshpande
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $594,516
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10856405

## Citation

> US National Institutes of Health, RePORTER application 10856405, Allosteric modulation of beta2- adrenoceptors in the treatment of asthma (1R01HL173113-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10856405. Licensed CC0.

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