Allosteric modulation of BETA2- adrenoceptors in the treatment of asthma

Active Project Grant Awarded Last action

Award ID
R01HL173113
Recipient
Awarding agency
Obligated
$3,358,481

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 64% complete
Place of performance
Philadelphia, PA 19107, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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 SS-agonists. At a molecular level, SS2AR 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 SS2AR-GS signaling relaxes airway smooth muscle (ASM), whereas SS2AR-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 SS2AR 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 SS2AR. Database screening identified small-molecule ligands that can bind to this site and modulate SS2AR-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 SS2AR-GS signaling by positive allosteric modulators (AMS) of SS2AR 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 SS2AR 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 SS2AR by the AMS. Aim 2 studies will elucidate the signaling (GS: GS activation, cyclic AMP generation, protein kinase a activation; -arrestin: arrestin recruitment, phosphorylation of P42/P44, loss of cell surface expression of SS2AR) 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 SS2AR and human ASM/airway epithelial cells, murine and human lung slices, and transgenic mice expressing human SS2AR in smooth muscle. Previous studies have demonstrated that -agonists promote asthma pathology in a SS2AR-arrestin-dependent manner in murine models. Enhancing canonical SS2AR-GS signaling may overcome the harmful effects of -agonists. We will assess the therapeutic benefit of AMS in a murine model of asthma and human lung slices (aim 3). We anticipate that the pams of 2AR will act in a biased fashion to augment desirable GS signaling and functional effects of -agonists, providing a basis for exploring a biased am-based therapeutic approach to improve the efficacy of current -agonists.

Transactions

Action Obligated Date
Amendment $555,192
Amendment $56,651
Amendment $509,870
Amendment $509,870
Amendment $56,650
Amendment $56,650
Amendment $537,866
Amendment $537,866
Original award $537,866

Subawards

Subrecipient Amount Awarded
University Of Maryland, Baltimore Statement of work: The MacKerell lab at the University of Maryland, Baltimore will supply the following. 1) Structural information on the conformational… $489,412
National Jewish Health The goal of the proposed work by Dr. Chu’s group at National Jewish Health is to utilize the human airway epithelial cell air-liquid interface culture… $154,168
National Jewish Health The goal of the proposed work by Dr. ChuÂ’s group at National Jewish Health is to utilize the human airway epithelial cell air-liquid interface culture… $46,560

Quick answers

Who received award R01HL173113?

R01HL173113 was awarded to Thomas Jefferson University by National Heart Lung and Blood Institute (National Institutes of Health) on April 1, 2024.

How much is award R01HL173113 worth?

$3,358,481 has been obligated on R01HL173113.

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