A multicenter research team developed the first drug to treat the uncontrolled secretion of mucins in the airways, which causes potentially life-threatening symptoms in millions of Americans with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), as well as lung disease resulting from cancer and cancer treatment.
“Mucus is a significant problem in pulmonary medicine, because in people with these common lung diseases, thick mucus can block the airways and cause symptoms ranging from a mild cough to very serious decreases in lung function,” said Burton Dickey, M.D. “Most drugs for these conditions work to reduce inflammation or expand the airways to help people breathe better, but mucus is the most serious issue. Our research has created the first drug that would stop the secretion of mucins in its tracks.”
Normally, mucins are gradually released into the airways, where they absorb water and form a thin layer of protective mucus that traps pathogens and is easily cleared by cilia. In muco-obstructive lung diseases, high volumes of mucins are suddenly released and, unable to absorb enough water, result in a thick mucus that can plug airways and impair lung function.
for the study “We built up a picture of what the secretory machinery looked like and we knew all of the major players,” Dickey said. “Once we had an idea of how all the pieces worked together, we determined synaptotagmin-2 (Syt2) was the best protein to target to block mucin secretion because it only becomes activated with a high level of stimulation. Therefore, blocking the activity of Syt2 should prevent sudden massive mucin release without impairing slow, steady baseline mucin secretion that is required for airway health.”
In this study, the researchers verified Syt2 as a viable therapeutic target protein in several types of preclinical models. Philip Jones, Ph.D., designed a hydrocarbon-stapled peptide, SP9, to block Syt2.
“An inhaled drug like this could help someone during an acute attack of airway disease by stopping the rapid secretion of mucin and, by extension, avoiding production of thick mucus. You can’t move air through an airway that’s plugged,” Dickey said. “In asthma, COPD and CF, it’s been shown that persistent plugs drive the most serious disease. Now we have a drug that could be very important if it’s shown to work in clinical trials.”
Lai, Y., Fois, G., Flores, J.R. et al. Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides. Nature, 2022 DOI: 10.1038/s41586-022-04543-1
University of Texas M. D. Anderson Cancer Center. “Novel therapy could help people with asthma, COPD, cystic fibrosis and cancer-related lung disease: Experimental drug reduces airway mucus that exacerbates common lung diseases.” ScienceDaily. ScienceDaily, 23 March 2022. <www.sciencedaily.com/releases/2022/03/220323125104.htm>.
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