Inhibition of TMEM16A Cl− Channel by Fungus‐Derived Penicillide in Airway Epithelial Cells

Abstract

Asthma represents one of the most common chronic diseases affecting around 300 million people with 250,000 annual deaths worldwide. It is characterized by airway inflammation, airway constriction, and mucus overproduction. The current treatments of asthma focus only on the first 2 characteristics without targeting on mucus overproduction. Transmembrane protein 16A (TMEM16A) is a Ca2+‐activated Cl− channel that, when activated, causes mucus production and secretion. Inhibition of TMEM16A activity effectively reduces mucus production along with its secretion. However, available TMEM16A inhibitors so far are synthetic compounds, or derived from plants which have limitation of large‐scale production. Therefore, this study aimed to identify novel TMEM16A inhibitor from fungal resources. A screening of >400 fungus‐derived natural compounds showed that N22, derivative of penicillide, potently inhibited ATP‐induced TMEM16A Cl− current with IC50 ~ 2 μM as analyzed by short‐circuit current measurement in human airway epithelial (Calu‐3) cell monolayers. Moreover, this inhibition was observed when TMEM16A is activated by Ionomycin (Ca2+ ionophore), or Eact (specific TMEM16A activator), suggesting that this inhibition was downstream to elevation of intracellular Ca2+ and might directly on TMEM16A molecule. As analyzed by MTT assays, inhibitory effect of N22 on TMEM16A‐mediated Cl− transport was not associated with cytotoxicity in Calu‐3 cells. Collectively, penicillides represent the first class of TMEM16A inhibitor from the fungi which may be beneficial for treatment of asthma resulting from mucus overproduction and secretion.Support or Funding InformationThis work was supported by the NSTDA Chair Professor grant (the Fourth Grant) of the Crown Property Bureau Foundation, Faculty of Science Mahidol University, Faculty of Graduate Studies Mahidol University and Medical Scholars Program, Mahidol University.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.