Fractionation of a herbal antidiarrheal medicine reveals Eugenol as an inhibitor of Ca2+-activated Cl- channel TMEM16A. Lopes-Pacheco M, Silva IAL, Turner MJ, et al. WebChannel gating is controlled by external factors like enzymes are controlled by modulators and effectors. official website and that any information you provide is encrypted The development of novel therapies for CF has been a success story with a real transformation in the disease prognosis, quality of life and life expectancy. However, T16inh-A01 and MONNA were found to also inhibit other members of this family, such as TMEM16B, in a dose-dependent manner.231 Ani9 and its derivative 5f232 are, therefore, presented as the most powerful and apparently selective TMEM16A inhibitors to date. 2013;168(1):253265. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. WebIon channels are integral proteins expressed in almost all living cells and are involved in muscle contraction and nutrient transport. The development of potent and more selective molecules that directly target TMEM16A may provide invaluable information on the role of this channel in CF and TMEM16A-related disorders. Lrias JR, Pinto MC, Botelho HM, et al. doi:10.1152/ajpcell.00384.2011, 131. Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia. Epub 2017 Dec 14. Despite such effects, denufosol failed to demonstrate improvement in lung function in individuals with CF in phase III trials.171,172 The lack of clinical efficacy may be related to its limited time of action (shorter than its expected half-life in the airways) and receptor desensitization.173 Furthermore, purinergic stimulation induces a transient increase in Ca2+ concentration that leads to a short-term activation of CaCCs, which might be insufficient to compensate for the lack of CFTR-mediated anion secretion.174 An increase in intracellular Ca2+ concentration may also lead to undesired side effects, such as increased mucus release from airway secretory cells.173 Duramycin (Moli1901/lancovutide) is an antibiotic that indirectly promotes CaCC activation by interacting with phosphatidylethanolamine at the PM175 and raising intracellular Ca2+ concentration.176 Although it was demonstrated to be safe and to improve lung function in individuals with CF in a phase II clinical study,177179 no further studies have evaluated the utility of duramycin for the treatment of CF. Moran O. Santos L, Mention K, Cavusoglu-doran K, et al. Science (80-). They play a critical role in the normal functioning of the excitable tissues of the nervous system and regulate the action potential and contraction events. J Cyst Fibros. Identification of the cystic fibrosis gene: chromosome walking and jumping. 2018;18(1):297. doi:10.1186/s12885-018-4197-9, 228. Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis. Anoctamin 1/TMEM16A controls intestinal Cl secretion induced by carbachol and cholera toxin. 2019;116(25):1249412499. Accordingly, additional efforts have been pursued to identify novel and more potent CFTR modulators that may benefit a larger CF population. The only new chloride transporter-targeted drugs that have emerged recently are modulators of mutant CFTR chloride channels that cause cystic fibrosis, which include the potentiator Ivacaftor, approved in 2012, and several correctors, the first approved in 2015. Targeting ion channels in cystic fibrosis. CFTR modulator drugs may be grouped into five main types according to their actions on CFTR mutations: read-through agents (for class I mutants), correctors (for class II mutants), potentiators (for classes III and IV mutants), amplifiers (for class V mutants, and possibly all others, except VII) and stabilizers (for class VI mutants). doi:10.1093/hmg/ddw290, 122. Toxicology. doi:10.1073/pnas.1214596109, 153. Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251). doi:10.3389/fphar.2019.00003, 34. Therefore, modulators that normalize Na+ homeostasis and, consequently, water, are likely to constitute a more appropriate approach.148, TMEM16A/ANO1 is a Ca2+-activated Cl channel (CaCC) expressed in various epithelia, including the airways, large intestine, salivary glands, pancreas, kidney and liver.33,149 It is also expressed in the nervous system,150,151 smooth muscles152 and tumor cells.153 Such a broad tissue expression justifies its multiple physiological roles, which include airway and exocrine gland secretion, smooth muscle contraction, neuronal signaling control and peristalsis regulation of gastrointestinal system.154 Furthermore, TMEM16A upregulation has been described in various types of cancer, such as gastrointestinal squamous cancer,155 head and neck squamous cell carcinoma,156 breast cancer157 and lung cancer,158 and it is generally associated with a poor prognosis.159. 2014;2(11):902910. WebIon channels continue to be an important therapeutic target for a range of indications, including arrhythmia, hypertension, local anesthesia, pain, stroke, epilepsy, depression, 2019;10(42):96639672. Although further studies are necessary to evaluate and optimize the efficacy of this therapy, its safety is currently under investigation on a phase I clinical study (NCT04375514). 2015;99:1435. 2019;10(1):3769. doi:10.1038/s41467-019-11784-8, 168. doi:10.1113/JP275175, 193. doi:10.1016/j.celrep.2019.01.068, 136. de Winter de Groot KM, Berkers G, Marck van der Wilt REP, et al. doi:10.1126/science.1191542, 110. Ion transport modulators are most commonly used to treat various noncommunicable diseases including diabetes and hypertension. 2019;294(48):1826918284. 2017;8(19):3185631863. CF affects over 90,000 individuals worldwide who are heterogeneously distributed, but with a higher incidence among Caucasians.11 Clinically, the disease has multi-organ involvement, being the respiratory disorder the major cause of morbidity and premature death.4,5,12,13 A cycle of airways dehydration and obstruction by a thick tenacious mucus, chronic inflammation and recurrent infections leads to epithelial injury, tissue remodeling and progressive loss of lung function, ultimately resulting in respiratory failure.4,5,12,13. ABBV-2737 is a second-generation corrector that was well-tolerated in phase I studies and demonstrated to rescue CFTR function in F508del/F508del HBE cells synergistically with VX-809, suggesting that these two molecules act by distinct mechanisms.73,74 In a phase IIa study, ABBV-2737 led to a reduction in sweat Cl concentration and improved ppFEV1, albeit modestly, in individuals with CF homozygous for F508del.75 ABBV-3221 is another second-generation corrector that demonstrated rescue of F508del-CFTR function with greater effects when in combination with corrector ABBV-2222 and potentiator ABBV-974 (formerly GLPG1837).76 Abbvie also has two additional investigational correctors (AC1 and AC2) that were shown to rescue processing and trafficking of other class II CFTR mutations, including G85E, M1101K and N1303K.46,77, Other investigational correctors include FDL-169 (Flatley Discovery)68 and RDR01752,78 which also appear to share the rescue mechanism with VX-809 and VX-661. Taylor-Cousar JL, Munck A, McKone EF, et al. Burris SK, Wang Q, Bulley S, Neeb ZP, Jaggar JH. Curr Mol Pharmacol. PLoS Genet. J Cyst Fibros. Chest. 1989;245(4922):10661073. 2013(27):536545. Shi S, Pang C, Guo S, et al. TMEM16A inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells. Kunzelmann K, Tian Y, Martins JR, et al. As it is also expected that more CFTR modulator drugs will become available for clinical use, there is a need to advance in the development of tools that enable predicting the clinical effectiveness of drugs by ex vivo assays performed in individual-derived specimens so as to select the best therapeutic option(s) for that individual a process termed theranostics, the principle underlying precision medicine.30,124 Such fact becomes even more relevant when treating individuals who have CF genotypes combining two different rare CFTR mutations (one in each allele) or even a complex allele. 2019;82:102050. doi:10.1016/j.ceca.2019.06.004, 154. Join researchers worldwide The company is identifying small molecule The widespread tissue distribution of ion channels, coupled with the plethora of physiological consequences of BI 1265162 is a pre-drug developed by Boehringer Ingelheim that directly inhibits ENaC. Veit G, Xu H, Dreano E, et al. For instance, some thiazole derivatives were found to act as both correctors and potentiators of F508del-CFTR, although the potentiator effect was lower in comparison to VX-770.97,98 Compounds containing a 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole core were able to efficiently rescue the function of F508del- and G551D-CFTR.99 A spiro[piperidine-4,1-pyrido[3,4-b]indole compound demonstrated potentiation activity for N1303K and I1234-R1239del CFTR with additive effects when in combination with VX-770.100 ASP-11 is an arylsulfonamide-pyrrolopyridine co-potentiator that acts synergistically with VX-770 in the rescue of F508del-, G551D-, N1303K- and W1282X-CFTR mutations in cell lines.101 The effects of ASP-11 were confirmed for N1303K in HBE cells, but not for W1282X.28,101 This considerably high number of compounds with distinct chemical structures provide a great source for the development of novel potentiator drugs. 2018;9:1176. doi:10.3389/fphar.2018.01176, 127. doi:10.1021/acsmedchemlett.9b00377, 77. Furthermore, a better understanding of the complexity of CF epithelial cell physiology and ion transport has enabled the pursue for alternative targets to compensate for the absence of CFTR function. Cell Physiol Biochem. Accessibility A more recent study screening over 660,000 molecules (Scripps Drug Discovery Library) for their ability to rescue G542X identified 188 compounds that rescue this PTC mutation when in combination with other modulators.52 These compounds are now being evaluated in primary cells from individuals with CF in order to validate the previous results and to analyze the translational read-through in a more physiologically relevant context. 2013;84(5):726735. We have engineered highly Donaldson SH, Solomon GM, Zeitlin PL, et al. These include the ability to penetrate the mucus barrier, the potency, the correct dose without off-target effects and a long half-life to achieve the best therapeutic effects. Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis. The first one proposes that there is altered pH of air surface liquid (ASL) in CF resulting from absence of CFTR-dependent HCO3 transport, which leads to inactivation of natural antimicrobial peptides in the ASL.138,139 The second model is based on the idea that loss of CFTR function leads to Na+ hyperabsorption by ENaC, leading to subsequent higher absorption of water and consequent ASL dehydration that causes impaired mucociliary clearance (MCC) in CF.140,141 As research data continue to support that a hyperactivation of ENaC occurs in CF cells, specific inhibition of ENaC function may represent a pathway to partially reverse the disruptive downstream effects of CF pathophysiology. doi:10.1016/j.jcf.2014.09.005, 87. See our editorial guidelines for everything you need to know about Frontiers peer review process. Leubitz A, Vanhoutte F, Hu M, et al. doi:10.1056/nejmoa1709847, 22. J Physiol. doi:10.1056/nejmoa1709846, 21. Ribbon diagram of two conformations of human CFTR: dephosphorylation, ATP-free conformation (left, PDB: 5UAK) (data from Liu et al) and phosphorylated, ATP-bound conformation (right, PDB: 6MSM) (data from Zhang et al). 2020;130(1):272286. 2012;303(11):C1173C1179. 2020;21(4):1488. doi:10.3390/ijms21041488, 251. ENaC inhibitors for the treatment of cystic fibrosis. J Pharmacol Exp Ther. Miller MR, Soave D, Li W, et al. doi:10.1038/ng.2745, 121. 2018;22(8):687701. Crotts D, Jan LY. Du K, Lukacs GL. 2018;24(11):17321742. Smith E, Dukovski D, Shumate J, Scampavia L, Miller JP, Spicer TP. 2018;19(1):201222. J Biol Chem. 2011;286(3):23652374. Front Pharmacol. For example, DIDS is also a potent inhibitor of anion exchangers and of the potassium/chloride co-transporter. The TMD segments cross the phospholipid bilayer and are connected by extracellular and intracellular loops, thus forming the channel pore through which anions are conducted.6,7 Conformational changes in the protein occur following ATP binding and/or hydrolysis in NBDs and phosphorylation of RD by protein kinase A (PKA) and protein kinase C (PKC), leading to channel opening.68 For this complex protein to attain its native functional state, domain folding and interdomain interactions have to occur by cooperative mechanisms.9,10. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Welch EM, Barton ER, Zhuo J, et al. Int J Mol Sci. doi:10.15252/embj.2018100300, 128. Veit G, Roldan A, Hancock MA, et al. Bethesda, MD 20894, Web Policies De Wilde G, Gees M, Musch S, et al. Liu S, Feng J, Luo J, Yang P, Brett TJ, Hu H. Eact, a small molecule activator of TMEM16A, activates TRPV1 and elicits pain- and itch-related behaviours. Am J Respir Crit Care Med. West RB, Corless CL, Chen X, et al. doi:10.1096/fj.201801333RRR, 199. The use of ex vivo individual-derived specimens has also become a powerful tool to evaluate novel drugs and predict their effectiveness in a personalized medicine approach. doi:10.1016/j.stem.2020.09.017, 135. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Anion-transport mechanism of a triazole-bearing derivative of prodigiosine: a candidate for cystic fibrosis therapy. 2014;592(18):40514068. However, as shown by previous studies,35,36,53 the combination of a read-through agent with other modulators that have complementary mechanisms may be required to efficiently rescue CFTR PTC mutations, as the incorporation of a random amino acid may produce a full-length protein which is still misfolded or dysfunctional. 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