Experts in airway bitter taste receptors and medicinal chemistry team up to advance a potential asthma and COPD treatment that works differently than existing bronchodilators

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TAMPA, Fla (Jan 4, 2021) — Despite the progress made in managing asthma and chronic obstructive pulmonary disease (COPD), poorly controlled symptoms for both respiratory diseases can lead to severe shortness of breath, hospitalizations or even death.

“Only about 50 percent of asthmatics, and an even lower percentage of people with COPD, achieve adequate control of lung inflammation and airway constriction with currently available medications,” said Stephen Liggett, MD, vice dean for research at the University of South Florida Morsani College of Medicine and a USF Health professor of medicine, molecular pharmacology and physiology, and biomedical engineering. “So, we’re clearly missing something from our drug armamentarium to help all these patients.”

Dr. Liggett’s laboratory has discovered several subtypes of bitter taste receptors (TAS2Rs) — G protein-coupled receptors expressed on human smooth airway muscle cells deep inside the lungs. In asthma and COPD, tightening of smooth muscles surrounding bronchial tubes narrows the airway and reduces air flow, and Dr Liggett’s lab found that these taste receptors open the airway when activated. They are now looking for new drugs to treat asthma and other obstructive lung diseases by targeting smooth muscle TAS2Rs to open constricted airways.

A promising bronchodilator agonist rises to the top

In a preclinical study published Nov. 5 in ACS Pharmacology and Translational Science, Dr. Liggett and colleagues identified and characterized 18 new compounds (agonists) that activate bitter taste receptor subtype TAS2R5 to promote relaxation (dilation) of human airway smooth muscle cells. The cross-disciplinary team found 1,10 phenanthroline-5,6-dione (T5-8 for short) to be the most promising of several lead compounds (drug candidates). T5-8 was 1,000 times more potent than some of the other compounds tested, and it demonstrated marked effectiveness in human airway smooth muscle cells grown in the laboratory.

For this drug discovery project, Dr. Liggett’s laboratory collaborated with Jim Leahy, PhD, professor and chair of chemistry at the USF College of Arts and Sciences, and Steven An, PhD, professor of pharmacology at the Rutgers Robert Wood Johnson Medical School.

In an extensive screening conducted previously, another research group identified only one compound that would bind to and specifically activate the TASR5 bitter taste receptor – although apparently with limited effectiveness. Using this particular agonist (called T5-1 in the paper) as a starting point, the team relied on their collective disciplines to devise new activators, aiming for a much better drug profile for administration to humans.

USF Health’s Stephen Liggett, MD

“The two key questions we asked were: ‘Is it possible to find a more potent agonist that activates this receptor?’ and ‘Is it feasible to deliver by inhalation given the potencies that we find?’” said Dr. Liggett, the paper’s senior author. “T5-8 was the bronchodilator agonist that worked best. There were a few others that were very good as well, so we now have multiple potential new drugs to carry out the next steps.”

The researchers developed screening techniques to determine just how potent and effective the 18 compounds were. A biochemical test assessed how well these new agonists activated TAS2R5 in airway smooth muscle cells isolated from non-asthmatic human donor lungs. Then, the researchers validated the effect on airway smooth muscle relaxation using a technique known as magnetic twisting cytometry, pioneered by Dr An.

“Team science” solves a structural problem

“The biggest challenge we faced was not having a 3-D crystal structure of TAS2R5, so we had no idea exactly how agonist T5-1 fit into this mysterious bitter taste receptor,” Dr. Liggett said. “By merging our strength in receptors, pharmacology, physiology, and drug development, our team was able to make the breakthrough.”

T5-8 was superior to all the other bronchodilator agonists screened, exhibiting a maximum relaxation response (50%) substantially greater than that of albuterol (27%). Albuterol belongs to the only class of direct bronchodilators (beta-2 agonists) available to treat wheezing and shortness of breath caused by asthma and COPD. However, this drug or its derivatives, often prescribed as a rescue inhaler, does not work for all patients and overuse has been linked to increased hospitalizations, Dr. Liggett said. “Having two distinct classes of drugs that work in different ways to open the airways would be an important step to help patients optimally control their symptoms.”

The ACS Pharmacology paper highlights the importance of translational research in bridging the gap between laboratory discoveries and new therapies to improve human health, he added. “This study yielded a drug discovery that successfully meets most of the criteria needed to advance the compound toward its first trial as a potential first-in-class bronchodilator targeting airway receptor TAS2R5.”

The study was supported by a grant from the NIH’s National Heart, Lung, and Blood Institute.

Tampa, FL (June 8, 2016) — The American Lung Association’s Airways Clinical Research Centers (ACRC) network has expanded the national reach of its clinical trials to enhance the quality of life for patients with asthma and chronic obstructive pulmonary disease (COPD). The University of South Florida (USF) — a continuous member of the Lung Association ACRC since its inception in 1999 — is among 17 centers across the country and one of only two centers in Florida.

The non-profit national network studies patients with airways diseases, specifically asthma and COPD, the latter of which includes emphysema and chronic bronchitis.

Asthma affects a high rate of Florida’s population, 8 percent of adults and 10 percent of children, and nearly 8 percent of Floridians have COPD, said Thomas Casale, MD, who assumes the role of principal investigator for USF’s Lung Association ACRC on July 1.

“Finding how best to treat these patients is a primary goal of the American Lung Association’s ACRC,” said Dr. Casale, professor of medicine and pediatrics in the Division of Allergy and Immunology, Department of Internal Medicine, USF Health Morsani College of Medicine.

                              Dr. Thomas Casale, left, and Dr. Richard Lockey

“Participation in this network gives our patients the opportunity to enroll in clinical studies designed to study these disorders and define optimal care for patients with asthma or COPD.  They can also expect to learn a lot about their disease and how best to manage their symptoms.”

Many studies published by investigators in the highly competitive Airways Clinical Research Centers network have been published in the New England Journal of Medicine or the Journal of the American Medical Association.

Richard Lockey, MD, director of the USF Health Division of Allergy and Immunology, has been USF’s ACRC principal investigator since the group began and will continue to collaborate on studies. Under his leadership, USF has participated in a variety of ACRC network clinical trials in which outcomes are helping shape the nature of care, including the:

• Anxiety and COPD Evaluation (ACE Trial) examining the relationship between anxiety, health status and prognosis to inform appropriate treatment strategies. Open at USF through June 30, 2016.
• Resistant Airway Obstruction in Children (REACH) study, investigating whether or not anti-inflammatory medications normally prescribed for children with asthma can help in the management of children with fixed airflow obstruction. Open at USF through June 30, 2017.
• Long-acting Beta Agonist Step-Down Study (LASST), investigating the best way to reduce treatment in well-controlled asthmatic patients.

• Continuous Positive Airway Pressure (CPAP) on Reducing Airway Reactivity in Asthmatics, a trial evaluating whether CPAP, an effective treatment for sleep apnea, can improve asthma control.

“Breathing is essential to life, and it’s vital for those suffering from lung disease to have access to the best treatment options available, and we get there through research,” said Harold P. Wimmer, National President and CEO of the American Lung Association.

“The Airways Clinical Research Centers Network attracts some of the best investigators nationwide, and by adding significantly to the expertise of the ACRC network, we will advance research to improve the quality of life for those living with both COPD and asthma.”

For more information on the American Lung Association’s ACRC, visit http://www.lung.org/our-initiatives/research/airways-clinical-research-centers/

About USF Health
USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and the USF Physicians Group. The University of South Florida is a Top 50 research university in total research expenditures among both public and private institutions nationwide, according to the National Science Foundation. For more information, visit www.health.usf.edu

About the American Lung Association
The American Lung Association is the leading organization working to save lives by improving lung health and preventing lung disease, through research, education and advocacy. The work of the American Lung Association is focused on four strategic imperatives: to defeat lung cancer; to improve the air we breathe; to reduce the burden of lung disease on individuals and their families; and to eliminate tobacco use and tobacco-related diseases. For more information about the American Lung Association, a holder of the Better Business Bureau Wise Giving Guide Seal, or to support the work it does, call 1-800-LUNGUSA (1-800-586- 4872) or visit: Lung.org.

Media contact:
Anne DeLotto Baier, USF Health Communications
abaier@health.usf.edu or (813) 974-3303