# Novel Biased Beta2-AR Ligands as Asthma Therapeutics

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $615,316

## Abstract

Agonists of the beta-2-adrenoceptor (b2AR), commonly referred to as b-agonists, have been a cornerstone of
asthma treatment for nearly half a century. Despite their utility, b-agonists used in asthma management have
problems, including functional tachyphylaxis, deterioration of asthma control, and mortality concerns. Moreover,
lingering safety concerns regarding long-acting b-agonists necessitate the concomitant use of corticosteroids.
The inability to understand why such problems exist and the failure to significantly improve b2AR pharmacology
is reflected by over 2 decades of NIH Program announcements declaring the need for safer, more efficacious
alternatives to asthma treatment. Over the last 2 decades our team has employed a robust combination of genetic
and molecular approaches to convincingly demonstrate that both endogenous and exogenous b-agonist promote
the asthma phenotype, and that the b2AR regulatory protein, b-arrestin-2 is critical to the limited efficacy, and
safety issues, associated with b-agonist use in asthma. Despite our work to date which constitutes compelling
proof of principle, a corrective pharmacological approach sufficiently feasible to advance has been unavailable
until now. In collaboration with colleagues at Thomas Jefferson University we have characterized a novel b2AR
agonist as well as b2AR allosteric modulator (AM) that provide the therapeutic signaling of b-agonists yet allow
the b2AR to avoid (pathology-inducing) engagement of b-arrestins. These compounds are the first b2AR
ligands/AMs capable of “biasing” b2AR to increase Gs protein signaling. We propose to use our preclinical in vivo
and cell-based models to: 1) establish that these novel compounds are superior to current b-agonists with respect
to mitigating the central features of asthma (airway inflammation and hyperresponsiveness (AHR)) while
maintaining bronchodilation function, 2) determine the specific cell type(s) through which these drugs work and
3) address a fundamental conundrum in the field of GPCR biology - do b-arrestins impact function and disease
by generating their own signal, or are their effects due to their inhibition of canonical b2AR signaling? In Aim 1
we will establish the ability of novel b2AR-biasing compounds to mitigate the asthma phenotype in in vivo and
cell-based models. In Aim 2 we will use using genetic and pharmacological approaches to establish epithelial
cell b2AR-arrestin biasing as critical to the permissive effect of b-agonist in promoting the asthma phenotype.
Finally, in Aim 3 we will establish the mechanisms by which novel b2AR biasing compounds regulate airway cell
functions that contribute to the asthma phenotype.

## Key facts

- **NIH application ID:** 10372196
- **Project number:** 5R01AI161296-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** RICHARD Agustin BOND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $615,316
- **Award type:** 5
- **Project period:** 2021-03-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372196

## Citation

> US National Institutes of Health, RePORTER application 10372196, Novel Biased Beta2-AR Ligands as Asthma Therapeutics (5R01AI161296-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10372196. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*