# Characterization of biased airway smooth muscle TAS2R agonists for treating asthma

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2022 · $541,620

## Abstract

Asthma remains a major public health issue worldwide, affecting all ages and ethnicities, with 50% of patients
experiencing inadequate control of the disease. Constricted airways from contraction of airway smooth muscle
is the major cause of airflow obstruction, and morbidity and mortality, in asthma. Despite this key point for
intervention, only one class of direct bronchodilators (-agonists) are available for treatment, and they are
suboptimal for many patients. We have discovered bitter taste receptors (TAS2Rs) on human airway smooth
muscle (HASM) cells which signal by a unique mechanism. When activated, TAS2Rs markedly relax HASM and
relieve airway obstruction that is otherwise resistant to -agonists. However, the known TAS2R agonists have
low affinity and evoke desensitization (tachyphylaxis) of the relaxation response over time via -arrestin
mechanisms. The overarching hypothesis is that TAS2R agonists with novel structures can be highly effective
in relaxing airways in an asthmatic milieu and yet not evoke tachyphylaxis. The broad long-term objectives are
to determine the 3D structures and binding sites of two TAS2Rs expressed on HASM (R5 and R14) and then
use these structures to perform virtual docking of an agnostic ultra-large compound library to identify potential
ligands. These hits will be examined in engineered model cells, but will be most intensely studied within the
context of the physiology of HASM cells, and human airways, under asthmatic conditions to delineate novel ways
to engage the receptor that are biased towards relaxation and away from desensitization. Aim 1 will
computationally determine the structures and binding sites for R5 and R14 using methods that include 13 trillion
combinations of the residues to determine favorable energy conformations of inactive and active states. The
structures will be used to dock compounds from a highly diverse library. These will be studied in Aim 2 to
determine potency and efficacy in genetically engineered model cells and in HASM cells from nonasthmatic and
asthmatic lungs. In Aim 3, the most favorable compounds will be studied to ascertain -arrestin engagement
and biasing away from desensitization in model cells, HASM cells, and human lungs under asthmatic conditions.
Results from Aims2/3 will be fed back into Aim1 to further refine a model of biased agonists for these HASM
TAS2Rs. Based on our preliminary data that support all three Aims, we will learn about the structural
requirements for biasing for these receptors. And, we anticipate that multiple highly effective agonists with
unexpected structures will be identified and that their bronchodilating properties in asthma will represent a new
class of powerful non-desensitizing agents for treating and preventing bronchospasm.

## Key facts

- **NIH application ID:** 10322110
- **Project number:** 5R01HL155532-02
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Stephen B Liggett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $541,620
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322110

## Citation

> US National Institutes of Health, RePORTER application 10322110, Characterization of biased airway smooth muscle TAS2R agonists for treating asthma (5R01HL155532-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10322110. Licensed CC0.

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