Drug discovery study identifies promising new compound to open
constricted airways

Date:
January 4, 2021
Source:
University of South Florida (USF Health)
Summary:
In a preclinical study, researchers identified and characterized
18 new compounds (agonists) that activate bitter taste
receptor subtype TAS2R5 to promote relaxation of human airway
smooth muscle cells. The cross- disciplinary team found 1,10
phenanthroline-5,6-dione (T5-8 for short) was 1,000 times more
potent than some of the other bronchodilator agonists tested,
and it demonstrated marked effectiveness in human airway smooth
muscle cells grown in the laboratory.



FULL STORY ========================================================================== 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.

"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."

========================================================================== Story Source: Materials provided by
University_of_South_Florida_(USF_Health). Original written by Anne
DeLotto Baier. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Donghwa Kim, Steven S. An, Hong Lam, James W. Leahy, Stephen
B. Liggett.

Identification and Characterization of Novel Bronchodilator
Agonists Acting at Human Airway Smooth Muscle Cell TAS2R5. ACS
Pharmacology & Translational Science, 2020; 3 (6): 1069 DOI:
10.1021/acsptsci.0c00127 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/01/210104094658.htm

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