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Biased β-Agonists Favoring Gs over β-Arrestin for Individualized Treatment of Obstructive Lung Disease

Tokmakova, Alina and Kim, Donghwa and Goddard, William A., III and Liggett, Stephen B. (2022) Biased β-Agonists Favoring Gs over β-Arrestin for Individualized Treatment of Obstructive Lung Disease. Journal of Personalized Medicine, 12 (3). Art. No. 331. ISSN 2075-4426. PMCID PMC8955194. doi:10.3390/jpm12030331. https://resolver.caltech.edu/CaltechAUTHORS:20220223-919593000

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Abstract

Signals from G-protein-coupled receptors (GPCRs) are the most frequently targeted pathways of currently prescribed therapeutics. Rather than being a simple switch, it is now evident that a given receptor can directly initiate multiple signals, and biasing to achieve signal selectivity based on agonist structure is possible. Biased agonists could direct therapeutically favorable pathways while avoiding counterproductive or adverse reaction pathways. For obstructive lung diseases, β₂-adrenergic receptor (β₂AR) agonists act at these receptors on airway smooth muscle (ASM) cells to open the airways by relaxing ASM, improving airflow and morbidity. However, these receptors signal to the G protein Gs (increasing cAMP and promoting relaxation), but also to β-arrestin (promoting desensitization and a loss of effectiveness). Indeed, β-agonist use is associated with adverse events in asthma pathogenesis and clinical outcomes which are related to desensitization. β-agonists favoring Gs coupling over β-arrestin binding would provide a means of tailoring bronchodilator therapy. In this review, we show how combinatorial methods with a 40 million compound agnostic library led to a new class of biased β-agonists that do not desensitize, providing an opportunity to personalize therapy in patients who experience poor efficacy or adverse effects from traditional balanced agonists.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.3390/jpm12030331DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955194/PubMed CentralArticle
ORCID:
AuthorORCID
Tokmakova, Alina0000-0001-5280-7621
Kim, Donghwa0000-0002-8994-8513
Goddard, William A., III0000-0003-0097-5716
Liggett, Stephen B.0000-0002-0128-3669
Additional Information:© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Received: 25 January 2022 / Revised: 14 February 2022 / Accepted: 17 February 2022 / Published: 22 February 2022. We thank Lauren K. Lujan and Hannah R. Strzelinski and our other collaborators for data generation for the original paper and Himeshkumar N. Patel for assistance in manuscript preparation. This research was funded by National Institutes of Health, grant number HL114471, HL142992, HL045967, and HL155532. Author Contributions. Conceptualization, investigation, formal analysis, writing-original draft preparation, writing-review and editing, A.T., D.K., W.A.G.III and S.B.L. All authors have read and agreed to the published version of the manuscript. The authors declare no conflict of interest.
Funders:
Funding AgencyGrant Number
NIHHL114471
NIHHL142992
NIHHL045967
NIHHL155532
Subject Keywords:β₂-adrenergic receptor; tachyphylaxis; G protein; desensitization; airway smooth muscle; G-protein-coupled receptor kinases
Other Numbering System:
Other Numbering System NameOther Numbering System ID
WAG1510
Issue or Number:3
PubMed Central ID:PMC8955194
DOI:10.3390/jpm12030331
Record Number:CaltechAUTHORS:20220223-919593000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220223-919593000
Official Citation:Tokmakova A, Kim D, Goddard WA III, Liggett SB. Biased β-Agonists Favoring Gs over β-Arrestin for Individualized Treatment of Obstructive Lung Disease. Journal of Personalized Medicine. 2022; 12(3):331. https://doi.org/10.3390/jpm12030331
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:113547
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:24 Feb 2022 20:54
Last Modified:23 Apr 2022 05:10

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