Discovery of Fungus-Derived Nornidulin as a Novel TMEM16A Inhibitor: A Potential Therapy to Inhibit Mucus Secretion in Asthma

References

• Song P, Adeloye D, Salim H, et al. Global, regional, and national prevalence of asthma in 2019: a systematic analysis and modelling study. J Glob Health. 2022;12:04052. doi:10.7189/jogh.12.04052
   PubMed Web of Science ®Google Scholar
• Dharmage SC, Perret JL, Custovic A. Epidemiology of asthma in children and adults. Front Pediat. 2019;7:246. doi:10.3389/fped.2019.00246
   PubMed Web of Science ®Google Scholar
• Most recent national asthma data; 2023. Available from: https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm. Accessed August 21, 2023.
   Google Scholar
• Toskala E, Kennedy DW. Asthma risk factors. Nt Forum Allergy Rhinol. 2015;5:S11–S16.
   PubMed Web of Science ®Google Scholar
• Lajiness JA-O, Cook-Mills JM. Catching our breath: updates on the role of dendritic cell subsets in asthma. Advan Bio. 2023;7:2200296. doi:10.1002/adbi.202200296
   Google Scholar
• Sinyor B, Concepcion Perez L. Pathophysiology of asthma; StatPearls; 2022.
   Google Scholar
• Poddighe D, Mathias CB, Freyschmidt EJ, et al. Basophils are rapidly mobilized following initial aeroallergen encounter in naïve mice and provide a priming source of IL-4 in adaptive immune responses. J Biol Regul Homeost Agents. 2014;28(1):91–103.
   PubMed Web of Science ®Google Scholar
• Yoshimoto T, Bendelac A, Watson C, Hu-Li J, Paul WE. Role of NK1.1+ T cells in a TH2 response and in immunoglobulin E production. Science. 1995;270(5243):1845–1847. doi:10.1126/science.270.5243.1845
   PubMed Web of Science ®Google Scholar
• Rubin BK, Priftis KN, Schmidt HJ, Henke MO. Secretory hyperresponsiveness and pulmonary mucus hypersecretion. Chest. 2014;146(2):496–507. doi:10.1378/chest.13-2609
   PubMed Web of Science ®Google Scholar
• Schroeder BC, Cheng T, Jan YN, Jan LY. Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell. 2008;134(6):1019–1029. doi:10.1016/j.cell.2008.09.003
   PubMed Web of Science ®Google Scholar
• Caputo A, Caci E, Ferrera L, et al. TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science. 2008;322(5901):590–594. doi:10.1126/science.1163518
   PubMed Web of Science ®Google Scholar
• Yang YD, Cho H, Koo JY, et al. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature. 2008;455(7217):1210–1215. doi:10.1038/nature07313
   PubMed Web of Science ®Google Scholar
• Rottgen TS, Nickerson AJ, Rajendran VM. Calcium-Activated Cl(-) Channel: insights on the molecular identity in epithelial tissues. Int J Mol Sci. 2018;19(5):1432. doi:10.3390/ijms19051432
   PubMed Web of Science ®Google Scholar
• Dam VS, Boedtkjer DM, Aalkjaer C, Matchkov V. The bestrophin- and TMEM16A-associated Ca(2+)- activated Cl(-) channels in vascular smooth muscles. Channels. 2014;8(4):361–369. doi:10.4161/chan.29531
   PubMed Web of Science ®Google Scholar
• Wang H, Zou L, Ma K, et al. Cell-specific mechanisms of TMEM16A Ca(2+)-activated chloride channel in cancer. Mol Cancer. 2017;16(1):152. doi:10.1186/s12943-017-0720-x
   PubMedGoogle Scholar
• Matchkov VV, Boedtkjer DM, Aalkjaer C. The role of Ca(2+) activated Cl(-) channels in blood pressure control. Curr Opin Pharmacol. 2015;21:127–137. doi:10.1016/j.coph.2015.02.003
   PubMed Web of Science ®Google Scholar
• Zhang CH, Li Y, Zhao W, et al. The transmembrane protein 16A Ca(2+)-activated Cl- channel in airway smooth muscle contributes to airway hyperresponsiveness. Am J Respir Crit Care Med. 2013;187(4):374–381. doi:10.1164/rccm.201207-1303OC
   PubMed Web of Science ®Google Scholar
• Okuyama K, Yanamoto S. TMEM16A as a potential treatment target for head and neck cancer. J Exp Clin Cancer Res. 2022;41(1):196. doi:10.1186/s13046-022-02405-2
   PubMed Web of Science ®Google Scholar
• Huang F, Zhang H, Wu M, et al. Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction. Proc Natl Acad Sci U S A. 2012;109(40):16354–16359. doi:10.1073/pnas.1214596109
   PubMed Web of Science ®Google Scholar
• Namkung W, Phuan PW, Verkman AS. TMEM16A inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells. J Biol Chem. 2011;286(3):2365–2374. doi:10.1074/jbc.M110.175109
   PubMed Web of Science ®Google Scholar
• Benedetto R, Cabrita I, Schreiber R, Kunzelmann K. TMEM16A is indispensable for basal mucus secretion in airways and intestine. FASEB J. 2019;33(3):4502–4512. doi:10.1096/fj.201801333RRR
   PubMed Web of Science ®Google Scholar
• Kondo M, Tsuji M, Hara K, et al. Chloride ion transport and overexpression of TMEM16A in a Guinea-pig asthma model. Clin Exp Allergy. 2017;47(6):795–804. doi:10.1111/cea.12887
   PubMed Web of Science ®Google Scholar
• Wang P, Zhao W, Sun J, et al. Inflammatory mediators mediate airway smooth muscle contraction through a G protein-coupled receptor-transmembrane protein 16A-voltage-dependent Ca(2+) channel axis and contribute to bronchial hyperresponsiveness in asthma. J Allergy Clin Immunol. 2018;141(4):1259–1268.e11. doi:10.1016/j.jaci.2017.05.053
   PubMed Web of Science ®Google Scholar
• Danielsson J, Kuforiji AS, Yocum GT, et al. Agonism of the TMEM16A calcium-activated chloride channel modulates airway smooth muscle tone. Am J Physiol Lung Cell Mol Physiol. 2020;318(2):L287–l295. doi:10.1152/ajplung.00552.2018
   PubMed Web of Science ®Google Scholar
• Centeio R, Ousingsawat J, Cabrita I, et al. Mucus release and airway constriction by TMEM16A may worsen pathology in inflammatory lung disease. Int J Mol Sci. 2021;22(15):7852. doi:10.3390/ijms22157852
   PubMed Web of Science ®Google Scholar
• Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res. 2001;2(2):66–70. doi:10.1186/rr40
   PubMed Web of Science ®Google Scholar
• Wang J, Haanes KA, Novak I. Purinergic regulation of CFTR and Ca(2+)-activated Cl(-) channels and K(+) channels in human pancreatic duct epithelium. Am J Physiol Cell Physiol. 2013;304(7):C673–84. doi:10.1152/ajpcell.00196.2012
   PubMed Web of Science ®Google Scholar
• Antonioli L, Blandizzi C, Pacher P, Hasko G. The purinergic system as a pharmacological target for the treatment of immune-mediated inflammatory diseases. Pharmacol Rev. 2019;71(3):345–382. doi:10.1124/pr.117.014878
   PubMed Web of Science ®Google Scholar
• Chavez J, Vargas MH, Martinez-Zuniga J, et al. Allergic sensitization increases the amount of extracellular ATP hydrolyzed by Guinea pig leukocytes. Purinergic Signal. 2019;15(1):69–76. doi:10.1007/s11302-019-09644-7
   PubMed Web of Science ®Google Scholar
• Gao ZG, Jacobson KA. Purinergic signaling in mast cell degranulation and asthma. Front Pharmacol. 2017;8(947). doi:10.3389/fphar.2017.00947
   Google Scholar
• Jang Y, Oh U. Anoctamin 1 in secretory epithelia. Cell Calcium. 2014;55(6):355–361. doi:10.1016/j.ceca.2014.02.006
   PubMed Web of Science ®Google Scholar
• Ayon RJ, Hawn MB, Aoun J, et al. Molecular mechanism of TMEM16A regulation: role of CaMKII and PP1/PP2A. Am J Physiol Cell Physiol. 2019;317(6):C1093–C1106. doi:10.1152/ajpcell.00059.2018
   PubMed Web of Science ®Google Scholar
• Tian Y, Kongsuphol P, Hug M, et al. Calmodulin-dependent activation of the epithelial calcium-dependent chloride channel TMEM16A. FASEB J. 2011;25(3):1058–1068. doi:10.1096/fj.10-166884
   PubMed Web of Science ®Google Scholar
• Evans CM, Kim K, Tuvim MJ, Dickey BF. Mucus hypersecretion in asthma: causes and effects. Curr Opin Pulm Med. 2009;15(1):4–11. doi:10.1097/MCP.0b013e32831da8d3
   PubMed Web of Science ®Google Scholar
• Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016;79(3):629–661. doi:10.1021/acs.jnatprod.5b01055
   PubMed Web of Science ®Google Scholar
• Tsukada K, Shinki S, Kaneko A, et al. Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones. Nat Commun. 2020;11(1):1830. doi:10.1038/s41467-020-15664-4
   PubMed Web of Science ®Google Scholar
• Ibrahim SRM, Mohamed GA, Al Haidari RA, El-Kholy AA, Zayed MF, Khayat MT. Biologically active fungal depsidones: chemistry, biosynthesis, structural characterization, and bioactivities. Fitoterapia. 2018;129:317–365. doi:10.1016/j.fitote.2018.04.012
   PubMed Web of Science ®Google Scholar
• Bernardini S, Tiezzi A, Laghezza Masci V, Ovidi E. Natural products for human health: an historical overview of the drug discovery approaches. Nat Prod Res. 2018;32(16):1926–1950. doi:10.1080/14786419.2017.1356838
   PubMed Web of Science ®Google Scholar
• Shamshuddin NSS, Mohd Zohdi R. Gelam honey attenuates ovalbumin-induced airway inflammation in a mice model of allergic asthma. J Tradit Complement Med. 2018;8(1):39–45. doi:10.1016/j.jtcme.2016.08.009
   PubMedGoogle Scholar
• Phainuphong P, Rukachaisirikul V, Phongpaichit S, et al. Depsides and depsidones from the soil-derived fungus Aspergillus unguis PSU-RSPG204. Tetrahedron. 2018;74(39):5691–5699. doi:10.1016/j.tet.2018.07.059
   Web of Science ®Google Scholar
• Pongkorpsakol P, Yimnual C, Chatsudthipong V, Rukachaisirikul V, Muanprasat C. Cellular mechanisms underlying the inhibitory effect of flufenamic acid on chloride secretion in human intestinal epithelial cells. J Pharmacol Sci. 2017;134(2):93–100. doi:10.1016/j.jphs.2017.05.009
   PubMed Web of Science ®Google Scholar
• Pongkorpsakol P, Pathomthongtaweechai N, Srimanote P, Soodvilai S, Chatsudthipong V, Muanprasat C. Inhibition of cAMP-activated intestinal chloride secretion by diclofenac: cellular mechanism and potential application in cholera. PLoS Negl Trop Dis. 2014;8(9):e3119. doi:10.1371/journal.pntd.0003119
   PubMed Web of Science ®Google Scholar
• Muanprasat C, Sirianant L, Soodvilai S, Chokchaisiri R, Suksamrarn A, Chatsudthipong V. Novel action of the chalcone isoliquiritigenin as a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor: potential therapy for cholera and polycystic kidney disease. J Pharmacol Sci. 2012;118(1):82–91. doi:10.1254/jphs.11153FP
   Web of Science ®Google Scholar
• Pongkorpsakol P, Buasakdi C, Chantivas T, Chatsudthipong V, Muanprasat C. An agonist of a zinc-sensing receptor GPR39 enhances tight junction assembly in intestinal epithelial cells via an AMPK-dependent mechanism. Eur J Pharmacol. 2019;842:306–313. doi:10.1016/j.ejphar.2018.10.038
   PubMed Web of Science ®Google Scholar
• Yimnual C, Satitsri S, Ningsih BNS, Rukachaisirikul V, Muanprasat C. A fungus-derived purpactin A as an inhibitor of TMEM16A chloride channels and mucin secretion in airway epithelial cells. Biomed Pharmacother. 2021;139:111583. doi:10.1016/j.biopha.2021.111583
   PubMed Web of Science ®Google Scholar
• Meyerholz DK, Griffin MA, Castilow EM, Varga SM. Comparison of histochemical methods for murine eosinophil detection in an RSV vaccine-enhanced inflammation model. Toxicol Pathol. 2009;37(2):249–255. doi:10.1177/0192623308329342
   PubMed Web of Science ®Google Scholar
• Cabrita I, Benedetto R, Wanitchakool P, et al. TMEM16A mediates mucus production in human airway epithelial cells. Am J Respir Cell Mol Biol. 2021;64(1):50–58. doi:10.1165/rcmb.2019-0442OC
   PubMed Web of Science ®Google Scholar
• Cabrita I, Benedetto R, Schreiber R, Kunzelmann K. Niclosamide repurposed for the treatment of inflammatory airway disease. JCI Insight. 2019;4(15). doi:10.1172/jci.insight.128414
   PubMed Web of Science ®Google Scholar
• Genovese M, Borrelli A, Venturini A, et al. TRPV4 and purinergic receptor signalling pathways are separately linked in airway epithelia to CFTR and TMEM16A chloride channels. J Physiol. 2019;597(24):5859–5878. doi:10.1113/jp278784
   PubMed Web of Science ®Google Scholar
• Scudieri P, Caci E, Bruno S, et al. Association of TMEM16A chloride channel overexpression with airway goblet cell metaplasia. J Physiol. 2012;590(23):6141–6155. doi:10.1113/jphysiol.2012.240838
   PubMed Web of Science ®Google Scholar
• Ebrahim HY, Elsayed HE, Mohyeldin MM, et al. Norstictic acid inhibits breast cancer cell proliferation, migration, invasion, and in vivo invasive growth through targeting C-met. Phytother Res. 2016;30(4):557–566. doi:10.1002/ptr.5551
   PubMed Web of Science ®Google Scholar
• Hao A, Guo S, Shi S, et al. Emerging modulators of TMEM16A and their therapeutic potential. J Membr Biol. 2021;254(4):353–365. doi:10.1007/s00232-021-00188-9
   PubMed Web of Science ®Google Scholar
• Hawksworth DL, Lucking R. Fungal diversity revisited: 2.2 to 3.8 million species. Microbiol Spectr. 2017;5(4). doi:10.1128/microbiolspec.FUNK-0052-2016
   PubMed Web of Science ®Google Scholar
• Blackwell M. The fungi: 1,2, 3. 5.1 million species? Am J Bot. 2011;98(3):426–438. doi:10.3732/ajb.1000298
   PubMed Web of Science ®Google Scholar
• Pham JV, Yilma MA, Feliz A, et al. A review of the microbial production of bioactive natural products and biologics. Front Microbiol. 2019;10:1404. doi:10.3389/fmicb.2019.01404
   PubMed Web of Science ®Google Scholar
• Keller NP. Fungal secondary metabolism: regulation, function and drug discovery. Nat Rev Microbiol. 2019;17(3):167–180. doi:10.1038/s41579-018-0121-1
   PubMed Web of Science ®Google Scholar
• Nielsen JC, Nielsen J. Development of fungal cell factories for the production of secondary metabolites: linking genomics and metabolism. Synth Syst Biotechnol. 2017;2(1):5–12. doi:10.1016/j.synbio.2017.02.002
   PubMed Web of Science ®Google Scholar
• Lenzi J, Costa TM, Alberton MD, Goulart JAG, Tavares LBB. Medicinal fungi: a source of antiparasitic secondary metabolites. Appl Microbiol Biotechnol. 2018;102(14):5791–5810. doi:10.1007/s00253-018-9048-8
   PubMed Web of Science ®Google Scholar
• Muangnil P, Satitsri S, Tadpetch K, et al. A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas. Biochem Pharmacol. 2018;150:293–304. doi:10.1016/j.bcp.2018.02.024
   PubMed Web of Science ®Google Scholar
• Braun OO, Lu D, Aroonsakool N, Insel PA. Uridine triphosphate (UTP) induces profibrotic responses in cardiac fibroblasts by activation of P2Y2 receptors. J Mol Cell Cardiol. 2010;49(3):362–369. doi:10.1016/j.yjmcc.2010.05.001
   PubMed Web of Science ®Google Scholar
• Schafer R, Sedehizade F, Welte T, Reiser G. ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells. Am J Physiol Lung Cell Mol Physiol. 2003;285(2):L376–85. doi:10.1152/ajplung.00447.2002
   PubMed Web of Science ®Google Scholar
• Sun Y, Birnbaumer L, Singh BB. TRPC1 regulates calcium-activated chloride channels in salivary gland cells. J Cell Physiol. 2015;230(11):2848–2856. doi:10.1002/jcp.25017
   PubMed Web of Science ®Google Scholar
• Tian Y, Schreiber R, Wanitchakool P, et al. Control of TMEM16A by INO-4995 and other inositolphosphates. Br J Pharmacol. 2013;168(1):253–265. doi:10.1111/j.1476-5381.2012.02193.x
   PubMed Web of Science ®Google Scholar
• Hawn MB, Akin E, Hartzell HC, Greenwood IA, Leblanc N. Molecular mechanisms of activation and regulation of ANO1-Encoded Ca(2+)-Activated Cl(-) channels. Channels. 2021;15(1):569–603. doi:10.1080/19336950.2021.1975411
   PubMed Web of Science ®Google Scholar
• Bonser LR, Zlock L, Finkbeiner W, Erle DJ. Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma. J Clin Invest. 2016;126(6):2367–2371. doi:10.1172/JCI84910
   PubMed Web of Science ®Google Scholar
• Hough KP, Curtiss ML, Blain TJ, et al. Airway Remodeling in Asthma. Front Med. 2020;7:191. doi:10.3389/fmed.2020.00191
   PubMed Web of Science ®Google Scholar
• Bai W, Liu M, Xiao Q. The diverse roles of TMEM16A Ca(2+)-activated Cl(-) channels in inflammation. J Adv Res. 2021;33:53–68. doi:10.1016/j.jare.2021.01.013
   PubMed Web of Science ®Google Scholar