For millions of patients suffering from asthma, a chronic respiratory disease, beta-agonists (-agonists) are the only medications that directly expand restricted airways and make breathing easier. These inhaled medicines activate and relax the b2-adrenergic receptors (2AR) on airway smooth muscle cells, dilating airways and boosting air flow.

However, for a considerable minority of asthmatics, existing -agonists are insufficient to open tightly constricted airways, and clinical advantages appear to diminish with time, leaving patients perpetually fighting with the disease.

“As regular use of β-agonists increases, the body becomes less sensitive to these bronchodilators,” says Stephen Liggett, MD, vice dean for research and a professor of medicine, molecular pharmacology and physiology, and biomedical engineering at the University of South Florida Health (USF Health) Morsani College of Medicine.

Known as tachyphylaxis or drug desensitization, this process contributes to poor asthma control, which leads to increased emergency department visits and hospitalizations, affecting the quality of life and resulting in increased medical costs and missed days of work and school.

Over tA multi-institutional research team lead by USF Health looked nearly 40 million compounds over the previous three years to find those that activated β₂AR (β-agonists) without triggering tachyphylaxis.

The researchers discovered one such agonist that was structurally unique from all other known β-agonists. Their preliminary research suggests that a separate class of β-agonists, known as biased agonists, could be used to treat asthma and other obstructive lung illnesses selectively. When administered on an as-needed basis, such biased agonists provide a therapeutic option without inducing the quick turndown of these receptors (2AR) or the even greater loss of effectiveness seen with chronic use.

Scientists with experience in biochemistry, physiology, and computational biology undertook the drug discovery study, which was published today in the Proceedings of the National Academy of Sciences of the United States (PNAS). To describe how this atypical agonist, known as C1-S, operates at the molecular level, the scientists used molecular modeling powered by high-speed, high-capacity supercomputers.

“This is the first β-agonist ever known to relax airway smooth muscle and treat asthma without any detectable tachyphylaxis and represents a significant breakthrough in asthma therapy,” says principal researcher Dr. Liggett, the PNAS paper’s senior author.

β2-adrenergic receptors are G protein-coupled receptors (GPCR) that mediate a variety of actions in airway smooth muscle cells. All of the current β-agonists used to treat asthma are non-biased. That means the medicine favors both activating a G-protein signaling pathway that improves airway smooth muscle cell relaxation (and hence better breathing) and engaging a beta arrestin (β-arrestin) signaling pathway that causes tachyphylaxis, which is an undesirable side effect.

“Beta-arrestin is a protein that upon interaction with the G protein-coupled receptor begins to uncouple (inhibit) the receptor from stimulating the clinically important signaling pathway we want to preserve,” explains Dr. Liggett.

“With unbiased beta agonists you have these dueling signaling processes essentially competing with each other.”

Although research is being conducted to develop biased agonists to assist reduce pain without addiction and to better treat specific cardiovascular illnesses with minimal adverse effects, no GPCR-biased agonists for asthma are currently being developed.

According to Dr. Liggett, the researchers undertook this large investigation with “no preconceived notions” about which substances could function best. Among their important discoveries:

• Of the 40 million compounds screened, 12 agonists activated the target receptor (β₂AR), stimulating cyclic AMP production that causes airway smooth muscle relaxation. But only one of these 12 (C1-S) appeared to be strongly biased away from the β-arrestin signaling that limits airway smooth muscle response (and thus drug effectiveness) due to receptor desensitization.
   
• Through a series of biochemical experiments, the researchers verified for the first time that it was possible for an agonist to “split the signal” mediated by a G coupled-protein receptor (β₂AR). This split preferentially activates, or switches on, a signaling pathway beneficial for treating obstructive lung disease rather than a pathway believed to be physiologically harmful, Dr. Liggett said.
   
• In addition to measuring signaling at the cellular level, the researchers employed the magnetic twisting cytometry, a method pioneered by co-author Steven An, PhD, at Rutgers University that measures changes in human airway smooth muscle cell relaxation and contraction. All the biochemistry results correlated with the physiological response the researchers expected — relaxation of airway smooth muscle without desensitization.
   
• Computer modeling and docking was performed by investigators at Caltech (William Goddard III, PhD, and now graduate student Alina Tokmakova). These studies helped identify molecular contact points between the receptor and biased agonist C1-S; some of these binding sites had not been seen with any other agonist before and thus point to the basis of the properties of this unique drug. The collection of 40 million compounds was assembled and maintained by Marc Giulianotti, PhD, of Florida International University.

According to Dr. Liggett, the researchers intend to test the safety and efficacy of their primary medication candidate C1-S in humans.

“Everyday we see breakthrough asthma symptoms in patients using albuterol, a beta-2 receptor agonist that is the cornerstone of treatment. When exacerbated, these symptoms sometimes require hospitalization, use of a ventilator, and occasionally even result in death,” says Kathryn S. Robinett, MD, assistant professor of medicine at the University of Maryland School of Medicine’s Division of Pulmonary and Critical Care Medicine, who was not involved in the research.

“A new class of beta-agonists that do not cause tachyphylaxis, like the one characterized in this study, could provide rapid relief and add a powerful tool to our belt in the treatment of asthma.”

Source: 10.1073/pnas.2026668118

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