Beta agonists (β agonists) are the only drugs that directly open the narrowed airways and facilitate breathing. Millions of people with asthma, Chronic respiratory disease.These inhalants activate b2-Adrenergic receptor (β)2AR) Relaxes airway smooth muscle cells, dilates the airways, and increases airflow.
However, in a significant proportion of asthma patients, the effectiveness of existing β-agonists is insufficient to open a tight airway, and the clinical benefits realized have diminished over time and are constantly suffering from illness. Looks like.
“The lack of more effective treatments to treat or prevent shortage of breath is a major problem for patients with severe to moderate asthma,” said Vice Dean of Research and Professor of Medicine, Molecular Pharmacology and Physiology. Stephen Rigget, Doctor of Medicine, said. University of South Florida Health (USF Health) Biomedical Engineering at Morsani Medical College. “As the regular use of β-agonists increases, the body becomes less sensitive to these bronchodilators.”
This process, known as tachyphylaxis or drug desensitization, contributes to poor asthma control, leads to increased emergency visits and hospitalizations, and impacts quality of life. Financial sacrifice Due to increased medical expenses and absence from work or school. Dr. Rigget’s lab is working with collaborators across the country to understand the mechanism of tachyphylaxis with the goal of improving β-agonists.
Over the last three years, a multicenter research team led by USF Health has studied 40 million compounds to identify compounds that activate β.2AR (β agonist) that does not cause tachyphylaxis. Researchers have discovered one such agonist that is structurally different from all known conventional β agonists. Their preclinical study Biased Agonists offer the potential to selectively treat asthma and other obstructive lung diseases. Such biased agonists are these receptors (β).2AR) Greater loss of efficacy observed when using the drug as needed or with chronic use.
Drug discovery research announced today Bulletin of the National Academy of Sciences (PNAS)Was conducted by scientists with expertise in biochemistry, physiology and computational biology.The team used molecular modeling driven by a fast, high-capacity supercomputer to create this atypical agonist named C1-S. Molecular level..
“This is the first beta agonist ever known to relax airway smooth muscle and treat asthma without detectable tachyphylaxis, and represents an important breakthrough in asthma treatment.” Said Principal Investigator Dr. Rigget. PNAS Lead author of the paper.
β2-adrenergic receptor G protein-coupled receptor (GPCR)Exists in the airways Smooth muscle cells Mediates various functions.All existing β agonists used to treat asthma Unbiased.. That is, the drug activates the G protein signaling pathway that promotes relaxation of airway smooth muscle cells (and thus facilitates breathing) and beta-arrestin (β-arrestin) signaling that leads to undesired consequences of tachycardia. It means equally supporting the involvement of the pathway.
“Beta-arrestin is a protein that interacts with G protein-coupled receptors to begin to isolate (inhibit) the receptors from stimulating clinically important signaling pathways that they want to preserve,” explains Dr. Liggett. bottom. “With an unbiased beta agonist, these duel signaling processes essentially compete with each other.”
Research is underway to design biased agonists that help relieve addiction-free pain and better treat certain cardiovascular diseases with minimal side effects. However, GPCR-biased agonists have not yet been developed for asthma.
Researchers undertook this large-scale study “without prejudice” about which compounds were most effective, Dr. Rigget said. Among their main findings:
- Of the 40 million compounds screened, 12 agonists are target receptors (β)2AR) stimulates cyclic AMP production, which causes relaxation of airway smooth muscle. However, only one of these 12 (C1-S) appears to be strongly biased from β-arrestin signaling, which limits airway smooth muscle response (and thus drug efficacy) due to receptor desensitization. I saw.
- Through a series of biochemical experiments, researchers have found that agonists are G-coupled protein receptors (β).2AR). This split gives priority to activation or switch-on. Signal transduction pathway Dr. Rigget said it is more beneficial in treating obstructive lung disease than routes that are considered physiologically harmful.
- In addition to measuring signal transduction at the cellular level, researchers are a method pioneered by Dr. Stephen Ann, co-author of Rutgers University, to measure changes in relaxation and contraction of human airway smooth muscle cells. Adopted magnetic twist cytometry. All biochemical results correlated with the physiological response researchers expected, that is, airway smooth muscle relaxation without desensitization.
- Computer modeling and docking was done by researchers at the California Institute of Technology (William Goddard III, Ph.D., now a graduate student, Alina Tokmakova). These studies helped identify molecular contact points between the receptor and the biased agonist C1-S. Some of these binding sites have not previously been found in other agonists, thus demonstrating the basis for the properties of this unique drug. A collection of 40 million compounds was collected and maintained by Dr. Marc Giulianotti of Florida International University.
Researchers are planning to evaluate the safety and efficacy of C1-S, a leading drug candidate, for its potential use in humans, Dr. Rigget said.
“Patients taking albuterol, the underlying beta-2 receptor agonist, have breakthrough asthma symptoms every day. When these symptoms worsen, hospitalization and the use of ventilators are recommended. It can be necessary and even fatal, “says Kathryn S. .. Robinett, MD, an assistant professor of lung and critical care medicine at the University of Maryland School of Medicine, was not involved in the study. “A new class of beta agonists that do not cause tachyphylaxis, as characterized in this study, may provide rapid relief in the treatment of asthma and add a powerful tool to our belt. . “
The co-authors of this study are Donghwa Kim and Ph.D. of the USF Health Morsani College of Medicine. Was Alina Tokmakova, a graduate student at the University of California, San Francisco.
Identification and characterization of atypical Gαs-biased βAR agonists that cannot induce tachyphylaxis in airway smooth muscle cells, Minutes of the National Academy of Sciences (2021). DOI: 10.1073 / pnas.2026668118..
University of South Florida
Quote: Biased beta agonists may provide better control of asthma and other obstructive lung diseases. Obtained from https://medicalxpress.com/news/2021-11-biased-beta- on November 22, 2021, according to the Drug Discovery Study. Agonist-Asthma-Obstructive-lung.html
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