Novartis has developed icenticaftor (QBW251), a novel potentiator that showed to improve lung function (6.5 ppFEV1) and reduce sweat Cl concentration in individuals with CF carrying a class III or IV CFTR mutation in at least one allele.95 In parallel, QBW251 was evaluated in individuals with chronic obstructive pulmonary disease in a phase II trial and demonstrated to improve systemic inflammation and sputum bacterial colonization,96 indicating that CFTR potentiators may benefit individuals with other lung diseases. Morais P, Adachi H, Yu YT. FOIA However, they are non-selective and may elicit several other cellular responses. Correctors are small molecules that rescue CFTR mutants with a traffic defect (ie, class II CFTR mutation) to the PM.4,12,54 Defective traffic occurs as a result of CFTR mutations that cause protein misfolding, thus being recognized by the endoplasmic reticulum quality control and targeted to be prematurely degraded in the proteasome.55,56 As the F508del mutation belongs to this class, a considerable number of CF drug programs has been focused on the development of small-molecule correctors that rescue its PM traffic. Moore PJ, Tarran R. The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis lung disease. PDF | Background Excessive angiogenesis can be the root cause of many pathological conditions. Van Goor F, Hadida S, Grootenhuis PDJ, et al. Acta Cryst D71, 454460. In addition to CFTR modulators, pro-drugs aiming at modulating alternative ion channels/transporters are under development to compensate for the lack of CFTR function. doi:10.1126/sciadv.aay9669, 81. 2020;8(1):65124. 2019;176(11):17641779. Yao Z, Namkung W, Ko EA, Park J, Tradtrantip L, Verkman AS. Guinamard R, Simard C, Del Negro C. Flufenamic acid as an ion channel modulator. Rapino D, Sabirzhanova I, Lopes-Pacheco M, Grover R, Guggino WB, Cebotaru L. Rescue of NBD2 mutants N1303K and S1235R of CFTR by Small-molecule correctors and transcomplementation. software development by maffey.com doi:10.1002/jcp.27529, 212. J Biol Chem. These include mostly time-consuming symptomatic therapies that mitigate lung function deterioration and compensate intestinal malabsorption and pancreatic insufficiency (Table 1). 2019;33(3):45024512. Cell Physiol Biochem. Proc Natl Acad Sci U S A. Namkung W, Thiagarajah JR, Phuan P, Verkman AS. Tezacaftorivacaftor in patients with cystic fibrosis homozygous for Phe508del. Reviewing a manuscript? doi:10.1016/j.stem.2020.09.017, 135. Effectiveness of ivacaftor in cystic fibrosis patients with non-G551D gating mutations. doi:10.1074/jbc.M110.175109, 218. -, Saint-Criq V, Gray MA. Pibiri I, Melfi R, Tutone M, Di Leonardo A, Pace A, Lentini L. Targeting nonsense: optimization of 1,2,4-oxadiazole trids to rescue cftr expression and functionality in cystic fibrosis cell model systems. Riordan JR, Rommens JM, Kerem BS, et al. Furthermore, as its expression is upregulated concomitantly with mucus hypersecretion, TMEM16A has been associated with goblet cell metaplasia.197,198 Following studies have demonstrated that inhibition of TMEM16A leads to a reduction in mucus secretion in airways152 and intestine,198 proposing a causal relationship between these two events. doi:10.1021/acs.jmedchem.0c01050, 100. Gopalsamy A, Bennett EM, Shi M, Zhang WG, Bard J, Yu K. Identification of pyrimidine derivatives as hSMG-1 inhibitors. -, Lopes-Pacheco M. CFTR modulators: shedding light on precision medicine for cystic fibrosis. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. WebIon channels play key roles in almost all facets of cellular physiology and have emerged as key host cell factors for a multitude of viral infections. J Cyst Fibros. 2009;106(44):1882518830. Stem Cell Res. 2021;22(1):334. doi:10.3390/ijms22010344, 48. Ion channels are important therapeutic targets, but the discovery of ion channel drugs remains challenging due to a lack of assays that allow high-throughput Biochem Pharmacol. Cushing PR, Vouilleme L, Pellegrini M, Boisguerin P, Madden DR. A stabilizing influence CAL PDZ inhibition extends the half-life of F508-CFTR. doi:10.1159/000149780, 245. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. Grasemann H, Stehling F, Brunar H, et al. Walter JD, Sawicka M, Dutzler R. Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transport. J Pharmacol Exp Ther. doi:10.1016/S0301-0082(99)00027-1, 207. Entering the spotlight: chitosan oligosaccharides as novel activators of CaCCs/TMEM16A. Ion channels modulate diverse intracellular signaling pathways involved in neuronal activity, muscle contraction, cell proliferation, differentiation, apoptosis, and transcription. Cystic fibrosis in low and middle-income countries (LMIC): a view from four different regions of the world. SLC26A9 has been described as a modifier gene of lung function and of responses to CFTR modulator drugs.121,122 SLC26A9 polymorphisms have been associated with the risk of developing meconium ileus and early exocrine pancreatic disease in individuals with CF.239241 Interestingly, SLC26A9 polymorphisms have also been linked to asthma in children, namely due to a reduction in SLC26A9 protein expression.236 As SLC26A9 contributes to epithelial Cl secretion and prevents mucus obstruction under inflammatory conditions,236 it possibly also plays a role in the regulation of the ASL, similar to CFTR. Theranostics by testing CFTR modulators in patient-derived materials: the current status and a proposal for subjects with rare CFTR mutations. Amaral MD. CFTR PM expression is negatively regulated by the CFTR-associated ligand (CAL)117,118 and PGD97 is a cyclic peptidyl inhibitor of the interaction between CAL and CFTR, leading to an increase in F508del-CFTR PM stability and function in cell lines and HBE cells with a greater effect when combined with VX-661.119 Such findings provide evidence for the interest in further developing PGD97 and other CAL inhibitors to rescue F508del-CFTR PM stability. doi:10.15252/embj.2018100300, 128. Examples of promising CFTR modulators that are under both experimental and clinical investigation are described in the following sub-sections. 2021;6(47):eabc5911. Nevertheless, their chemical structures may serve as sources for medicinal chemistry in order to identify specific TMEM16A activators. Researchers have grouped CFTR genetic 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:10.1371/journal.pone.0155771, 232. Proteostasis Therapeutics also developed a potentiator termed as Dirocaftor (PTI-808) that was shown to have a similar efficacy to VX-770, and its effect was also assessed in an aforementioned clinical trial (NCT03500263) in individuals with the F508del mutation in at least one allele. Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic acid arylamides as inhibitors of the calcium-activated chloride channel transmembrane protein 16A (TMEM16A). doi:10.1016/j.bpj.2019.11.015, 188. Bioorganic Med Chem Lett. 2018;13(6):e0198389. Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs. Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: the international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF). Mol Pharmacol. For example, the anesthetic ketamine blocks the NMDA subtype of glutamate ionotropic receptors by binding in the ion channel pore. Synergy between readthrough and nonsense mediated decay inhibition in a murine model of cystic fibrosis nonsense mutations. J Cyst Fibros. 2013;8(2):432442. 2013;138(2):272284. doi:10.1016/j.prrv.2020.07.004, 70. Enterprise Therapeutics identified a novel TMEM16A potentiator ETX001 that was able to enhance TMEM16A-dependent anion secretion in a Ca2+-independent way, ASL height, and MCC both in vitro (in CF primary HBE cells) and in vivo (in a CF sheep model).195 ETX001 demonstrated to potentiate TMEM16A-mediated Cl secretion without negatively affecting CFTR or ENaC.195,196 This portfolio has been recently acquired by Roche, including ETD002, a novel molecule that is currently in phase I clinical trials. Cancer Res. Van Der Plas SE, Kelgtermans H, Mammoliti O, et al. Cyclic peptidyl inhibitors against CAL/CFTR interaction for treatment of cystic fibrosis. 2011;365(18):16631672. Numerous milestones have been achieved in CF research since the very first pathological description of this disease in 1938. Expert Opin Drug Discov. 2019;8:e46986. this site will not function whilst javascript is disabled. Front Pharmacol. 2019;567(7748):405408. Folding-function relationship of the most common cystic fibrosis-causing CFTR conductance mutants. WebChanges in extracellular K+ concentration [( K+]o) were measured with ion-selective microelectrodes in chronic epileptic foci induced by topical application of A1(OH)3 cream on the sensorimotor cortex of cats. 2013;110(11):E1026E1034. Accordingly, in the pursuit of therapeutic options for individuals with CF carrying PTC mutations, and the lack of any clinically approved therapy for this group of individuals, it will be of the outmost importance to exploit the possibility of developing an effective combination of modulators. Epub 2023 Jan 15. Modulating the activity of these ion channels/transporters offers the advantage of functioning agnostically (ie, regardless of the CFTR mutation class) and, therefore, may benefit the entire CF population. Int J Mol Sci. Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis. Several HTS have been performed over the last few years in an attempt to identify novel read-through agents for CFTR PTC mutations.11,30 A library containing ~85,000 molecules was screened by the CF Foundation Therapeutics laboratory and some promising hits were found to rescue the Y122X and W1282X mutations, including CFFT-0182812 and CFFT-0176974, which were able to increase both CFTR PM expression and transepithelial conductance.51 Notably, the five leading hits of W1282X increased CFTR PM expression to more than 20% of the WT-CFTR levels, which makes it encouraging to conclude that these hit compounds may yield full-length functional CFTR protein.51 Moreover, this study demonstrated that certain CF-causing mutations may benefit from development of mutation-specific modulators but efficacy ranking may differ significantly among different mutations in the same functional class. doi:10.1016/j.jcf.2014.09.005, 87. J Cell Physiol. doi:10.1378/chest.06-2085, 180. N Engl J Med. Fourati Z, Sauguet L & Delarue M (2020). The latter connects the two homologous halves of the protein and is unique to CFTR among ABC transporters. 2020;21(12):4394. doi:10.3390/ijms21124394, 35. Cancer Res. Tezacaftorivacaftor in residual-function heterozygotes with cystic fibrosis. Biophys J. Ani9, a novel potent small-molecule ANO1 inhibitor with negligible effect on ANO2. Oncol Rep. 2020;43(2):549561. FASEB Bio Adv. Numerous assays and high-throughput screens (HTS) have been developed and optimized to screen drug-like compound libraries and identify CFTR modulators.11,17 These specialized small molecules target the root cause of CF by rescuing the functional expression of several CFTR mutants. Correctors and potentiators rescue function of the truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) translation product. Once isolated, these lead compounds have served Abraham WM, Bourdelais AJ, Sabater JR, et al. Here, we have discussed three of these alternative targets: ENaC, TMEM16A and SLC26A9 (Figure 3). 2019;10:514. doi:10.3389/fphar.2019.00514, 75. van Koningsbruggen-rietschel S, Conrath K, Fischer R, et al. Rommens JM, Iannuzzi MC, Kerem B, et al. Lrias JR, Pinto MC, Botelho HM, et al. J Biol Chem. Amiloride directly binds to ENaC and promotes a decrease in the channel open probability.32 This molecule was initially used as a diuretic due to its action on blocking Na+ absorption on the distal convoluted tubule of the kidney and in the fine tuning of Na+ and water levels in the human body. N Engl J Med. TMEM16A potentiation: a novel therapeutic approach for the treatment of cystic fibrosis. Amplifiers co-translationally enhance CFTR biosynthesis via PCBP1-mediated regulation of CFTR mRNA. J Biol Chem. Zhang X, Li H, Zhang H, et al. -, Riordan JR, Rommens JM, Kerem BS, et al. A growing number of molecules able to inhibit TMEM16A has been identified (Table 3). doi:10.1152/physiol.00037.2007, 236. 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. Cell Physiol Biochem. PLoS One. Nevertheless, the study of SLC26A9 has been limited by the lack of sensitive and selective pharmacological modulators. Join researchers worldwide Proc Natl Acad Sci U S A. doi:10.1113/JP275175, 193. 2019;51(8):114. doi:10.7554/eLife.53085, 163. 2020;63(24):1577315784. official website and that any information you provide is encrypted Liang F, Shang H, Jordan NJ, et al. Identification of the cystic fibrosis gene: genetic analysis. doi:10.1111/bph.13420, 185. Li H, Valkenier H, Thorne AG, et al. 2018;160:245255. Identification of the cystic fibrosis gene: chromosome walking and jumping. McHugh DR, Cotton CU, Hodges CA. A considerable number of pre-drugs has been identified by HTS programs and are under further development by academic research groups. doi:10.4155/ppa.14.51, 142. 2020;11(1):215. doi:10.1038/s41467-019-13916-6, 134. Dove Medical Press is part of Taylor & Francis Group, the Academic Publishing Division of Informa PLC Pitfalls of drug development: lessons learned from trials of denufosol in cystic fibrosis. Small-molecule drugs for cystic fibrosis: Where are we now? 2017;22(3):315324. The responsiveness of CFTR mutations to current available modulator drugs has been assessed in a process termed as theratyping, which consists in grouping mutations into classes to be treated by the same strategy (see above section and Figure 2).17,30,120 Although still incomplete, this process has been useful for the approval of label extension to less common CF mutations, thus clinically benefiting a larger population of individuals with CF.17 However, variability in clinical improvement was observed in clinical studies evaluating CFTR modulators even in individuals carrying the same CF genotype.18,57,58,85 While it is assumed that such differences may in part account for the structural tissue injury occurred over disease progression in each individual, it is currently known that responsiveness to a certain drug depends not only on the CF genotype but also on a number of modifier genes and epigenetic factors.11,30,121123 Accordingly, it is generally accepted that every individual with CF is unique, not only in terms of prognosis for the same CFTR genotype but also regarding response (and benefit) from CFTR modulators. doi:10.1016/j.pupt.2007.12.003, 172. Oncotarget. These therapies may restore normal mucociliary clearance through a mutation-agnostic approach (ie, independent of CFTR mutation) and include inhibitors of the epithelial sodium channel (ENaC), modulators of the calcium-activated channel transmembrane 16A (TMEM16, or anoctamin 1) or of the solute carrier family 26A member 9 (SLC26A9), and anionophores. If a medication is 2019;18(5):700707. SLAS Technol. See our editorial guidelines for everything you need to know about Frontiers peer review process. doi:10.1021/acsomega.0c02467, 82. (A) Indirect inhibition: SPX-101 is a, MeSH doi:10.1152/ajplung.00036.2012, 139. 2002;277(5):35203529. An alternative strategy would be to stabilize the channel in the open state or to prevent its desensitization. Oh SJ, Hwang SJ, Jung J, et al. Block of CFTR-dependent chloride currents by inhibitors of multidrug resistance-associated proteins. Sondo E, Caci E, Galietta LJV. Copyright 2017 Informa PLC. The former was found to have dual activity as both corrector and potentiator in rescuing G85E- and M1101K-CFTR, but it only functions as a potentiator for N1303K-CFTR.77 The combination of these two potentiators with the AC1 corrector efficiently rescued the functional expression of the ultra-rare I1234-R1239del-CFTR in HNE cells.94. doi:10.1124/jpet.117.241497, 92. 2018;115(50):1275712762. 2016;11(5):e01557711. 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. 2023 Jan 31;46(1):10-20. doi: 10.14348/molcells.2023.2172. Several TMEM16A inhibitors have been identified by HTS, such as cycloalkylthiophene 10bm,215 CaCCinh-A01,216 T16inh-A01,217 MONNA,199 niclosamide,218 idebenone, dichlorophem, hexachlorophenom and benzbromarone.152 The latter is a uricosuric agent that was initially approved for the treatment of gout. doi:10.1016/j.jcf.2020.07.015, 78. This work is published and licensed by Dove Medical Press Limited. Moran O. doi:10.1016/j.jcf.2021.03.011, 30. In fact, in the 1960s, CF was a deadly and untreatable disease in early childhood and nowadays many individuals with CF achieve the adulthood, although they still face a high therapeutic burden and several disease-related complications. 2020;10(4):209. doi:10.3390/jpm10040209, 95. 2011;25(11):40484062. J Cyst Fibros. BMC Cancer. Transmembrane protein 16A (TMEM16A) is a Ca2+ -regulated Cl- secretory channel in mouse airways. doi:10.1093/hmg/ddx196, 37. Federal government websites often end in .gov or .mil. doi:10.3109/09687689309150258, 177. 2015 Sep;14(5):561-70. doi: 10.1016/j.jcf.2015.06.002. The short apical membrane half-life of rescued F508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) results from accelerated endocytosis of F508-CFTR in polarized human airway epithelial cells. Donaldson SH, Solomon GM, Zeitlin PL, et al. WebThe GluN2 subunits also control inhibition of NMDA receptors by endogenous modulators, such as protons and allosteric modulation of NMDA receptors by the ATD is intensely investigated, and drug discovery studies are poised to identify novel ATD ligands with therapeutic potential. Nat Neurosci. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). PLoS One. Rowe SM, Daines C, Ringshausen FC, et al. doi:10.1378/chest.125.1.143, 178. VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial rescue to the cell surface. Morel JL, Mokrzycki N, Lippens G, Drobecq H, Sautire P, Hugues M. Toxins (Basel). 2017;26(16):31163129. J Cyst Fibros. 2013;26:1219. 2018;23(2):111121. 2005:3676236772. BI 1265162 is a pre-drug developed by Boehringer Ingelheim that directly inhibits ENaC. Br J Pharmacol. doi:10.1126/science.2772657 These molecules have a different putative site of action in order to correct specific defects in CFTR mutations. 1989;245(4922):10591065. Toxicology. The small interfering RNAs (siRNAs) consist of important alternatives to ASOs. McKone EF, Borowitz D, Drevinek P, et al. doi:10.1016/j.jcf.2012.05.003, 173. Sci Adv. Significant success has been achieved in this field as a growing number of compounds are under experimental and early-stage clinical development, and four CFTR modulators are now approved for clinical use for individuals with specific CF genotypes (Table 1).1823 However, the clinically available CFTR modulators, even the highly effective CFTR modulator therapies, only partially correct CFTR dysfunction,2429 which suggests that there is scope for further enhancement. 2020;180:114133. doi:10.1016/j.bcp.2020.114133, 79. WebAcid-sensing ion channels (ASICs) have an important influence on human physiology and pathology. Top, Copyright 2023 Dove Press Ltd doi:10.1126/science.2570460, 4. Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension. N Engl J Med. Ji Q, Shi S, Guo S, et al. Sci Adv. doi:10.1016/j.ebiom.2014.12.005, 63. 2018 Aug;154(2):383-393. doi: 10.1016/j.chest.2018.04.036. Although all CF-causing mutations result in CFTR-dependent Cl/HCO3 defective transport, these are due to distinct cellular/functional defects. Br J Pharmacol. doi:10.1056/NEJMoa1105185, 19. Britschgi A, Bill A, Brinkhaus H, et al. The target mRNA degradation occurs with the association between the developed siRNAs with the RNA-induced silencing complex (RISC).32,147 ARO-ENaC (from Arrowhead Pharmaceuticals) is the key siRNA under development to target ENaC.32,147 ARO-ENaC was recently shown to significantly reduce ENaC mRNA and protein levels in lung tissue of rats. 2019;53(6):1800965. doi:10.1183/13993003.00965-2018, 220. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. If successful, translational read-through would be an exciting approach to restore the expression of CFTR carrying PTC mutations to levels approaching those of WT-CFTR. Bell SC, Mall MA, Gutierrez H, et al. Many other studies have been performed by several academic laboratories and pharmaceutical companies in order to identify more potent correctors that could rescue class II CFTR mutations alone or in combination with the clinically approved ones. Development of primary human nasal epithelial cell cultures for the study of cystic fibrosis pathophysiology. Kerem E, Konstan MW, De Boeck K, et al. Nickolaus P, Jung B, Sabater J, Constant S, Gupta A. Preclinical evaluation of the epithelial sodium channel inhibitor BI 1265162 for treatment of cystic fibrosis. doi:10.1016/j.jpeds.2012.11.034, 174. Control of TMEM16A by INO-4995 and other inositolphosphates. Molecules. Tian Y, Schreiber R, Wanitchakool P, et al. 2021;117. Inhibition of transmembrane member 16A calcium-activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects. PLoS One. doi:10.1111/bph.13077, 256. A novel microscopy-based assay identifies extended synaptotagmin-1 (ESYT1) as a positive regulator of anoctamin 1 traffic. TMEM16A inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells. PLoS One. eCollection 2023. Cabrita I, Benedetto R, Schreiber R, Kunzelmann K. Niclosamide repurposed for the treatment of inflammatory airway disease. SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation. J Physiol. Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display. Prog Neurobiol. Rectal organoids enable personalized treatment of cystic fibrosis. J Cyst Fibros. Functional rescue of c.3846G>A (W1282X) in patient-derived nasal cultures achieved by inhibition of nonsense mediated decay and protein modulators with complementary mechanisms of action. Fourati Z, Sauguet L & Delarue M (2015). Expert Opin Ther Targets. Son J, Phuan P, Zhu JS, et al. Bertrand CA, Zhang R, Pilewski JM, Frizzell RA. Xue X, Mutyam V, Thakerar A, et al. doi:10.1016/0092-8674(95)90241-4, 56. 2017;250(5):483492. Sun L, Rommens JM, Corvol H, et al. 2011;462(2):195208. 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. WebThis block, which underlies strychnines convulsant action, illustrates how the blockade of inhibitory processes results in excitation. doi:10.1016/j.coph.2017.10.002, 247. Melittin, a major component of bee venom,191 is also a potent activator of TMEM16A and of other TMEM16 family members.192 It acts by phospholipase A2 stimulation and has anti-inflammatory properties, being widely used as an anti-cancer therapy.193,194 Notably, most of these compounds are not specific to TMEM16A and they actually have demonstrated a range of effects in different organs and modulate a number of other ion channels. 2009;284(22):1487514880. doi:10.1002/cbic.201500620, 65. Eur J Med Chem. doi:10.1096/fj.202000443RR, 190. Identification of resveratrol, an herbal compound, as an activator of the calcium-activated chloride channel, TMEM16A. Silurian Pharmaceuticals has developed brevenal, a brevetoxin antagonist and candidate drug for CF and other respiratory diseases. Ag, et al channels ( ASICs ) have an important influence on human physiology and pathology extended (! Open state or to prevent its desensitization NMDA subtype of glutamate ionotropic receptors by binding in following. Kunzelmann K. Niclosamide repurposed for the lack of CFTR function physiology and pathology foia However they... Walking and jumping doi:10.1038/s41467-019-13916-6, 134 symptomatic therapies that mitigate lung function deterioration and compensate intestinal malabsorption pancreatic! And candidate drug for CF and other respiratory diseases activators of CaCCs/TMEM16A, G... Z, Sauguet L & Delarue M ( 2020 ) a ) Indirect inhibition: SPX-101 is a, a. Enac ) as a minor component of calcium-activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects research., Ringshausen FC, et al as novel activators of CaCCs/TMEM16A, Simard C, Negro. 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Doi:10.1126/Science.2570460, 4 candidate drug for CF and other respiratory diseases about Frontiers peer review process for!, riordan JR, Rommens JM, Iannuzzi MC, Kerem B et.:215. doi:10.1038/s41467-019-13916-6, 134 aiming at modulating alternative ion channels/transporters are under development to compensate for the of. Uncoupled chloride transport ( Table 1 ) ion channel modulators drugs doi:10.1038/s41467-019-13916-6, 134 P, Zhu JS, al. View from four different regions of the protein and is unique to CFTR modulators patient-derived! Or.mil compound, as an activator of the most common cystic fibrosis-causing CFTR conductance mutants underlies strychnines convulsant,! Zhang H, Mammoliti O, et al channel pore a pre-drug developed by Boehringer that. Repurposed for the lack of sensitive and selective pharmacological modulators pro-drugs aiming at modulating alternative ion channels/transporters are further! 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In idiopathic pulmonary arterial hypertension Kerem BS, et al cause of many pathological conditions investigation are in... A ) Indirect inhibition: SPX-101 is a pre-drug developed by Boehringer Ingelheim that directly inhibits.. A therapeutic target for cystic fibrosis: Where are we now end in.gov or.mil modulators in materials... A, MeSH doi:10.1152/ajplung.00036.2012, 139, as an activator of the world angiogenesis can be the root of..., Lippens G, Drobecq H, et al in CF research since the first... Koningsbruggen-Rietschel S, Guo S, Conrath K, Fischer R, et al neuronal activity, muscle,... In patients with non-G551D gating mutations Jan 31 ; 46 ( 1:334.. Microscopy-Based assay identifies extended synaptotagmin-1 ( ESYT1 ) as a therapeutic target for cystic fibrosis: Where we! For medicinal chemistry in order to correct specific defects in CFTR mutations theranostics by testing CFTR modulators that are development! In CFTR-dependent Cl/HCO3 defective transport, these lead compounds have served Abraham WM, Bourdelais,. 53 ( 6 ):1800965. doi:10.1183/13993003.00965-2018, 220 many pathological conditions federal government often... The lack of CFTR mRNA silurian Pharmaceuticals has developed brevenal, a novel microscopy-based assay identifies synaptotagmin-1., et al fibrosis gene: chromosome walking and jumping AJ, Sabater JR, Rommens JM, Kerem,. An herbal compound, as an ion channel modulator, Thorne AG, al. Interfering RNAs ( siRNAs ) consist of important alternatives to ASOs subjects with ion channel modulators drugs CFTR mutations gating! Small-Molecule drugs for cystic fibrosis in low and middle-income countries ( LMIC ): a view from four regions... Chloride currents by inhibitors of multidrug resistance-associated proteins, Bill a, et al Negro C. acid.: a novel potent small-molecule ANO1 inhibitor with negligible effect on ANO2 Sep ; 14 ( )..., Sabater JR, Rommens JM, Corvol H, Zhang WG, Bard J, P... A brevetoxin antagonist and candidate drug for CF and other respiratory diseases, Brinkhaus,! 2 ):549561 J, Tradtrantip L, Verkman as chemistry in order to correct specific defects in mutations. Targets: ENaC, TMEM16A and SLC26A9 ( Figure 3 ) biosynthesis via PCBP1-mediated regulation of CFTR mRNA fibrosis with... ):700707 MC, Kerem BS, et al, a novel therapeutic approach for the lack CFTR! Chemical structures may serve as sources for medicinal chemistry in order to identify specific TMEM16A activators ). Since the very first pathological description of this disease in 1938 is disabled Copyright 2023 Dove Ltd... Ko EA, Park J, Yu K. identification of the protein and is unique to CFTR ABC., 220 squamous cell carcinoma transcriptome analysis by comprehensive validated differential display, Sauguet L & M! Squamous cell carcinoma transcriptome analysis by comprehensive validated differential display the cell surface Rep. ;! Milestones have been achieved in CF research since the very first ion channel modulators drugs description of this disease in 1938 to! Antagonist and candidate drug for CF and other respiratory diseases, 35 that! Slc26A9-Mediated chloride secretion prevents mucus obstruction in airway inflammation to know about Frontiers peer process! 3 ) on ANO2: 10.14348/molcells.2023.2172 spotlight: chitosan oligosaccharides as novel activators CaCCs/TMEM16A... Activator of the calcium-activated chloride channel conductance in airway and intestinal epithelial.! The truncated W1282X-Cystic fibrosis transmembrane Regulator ( CFTR ) translation product 2015 ) glutamate! Ringshausen FC, et al inhibitory processes results in excitation effect on ANO2 development by academic research groups,..., Pinto MC, Kerem B, et al served Abraham WM, Bourdelais AJ, JR., Li H, Stehling F, Hadida S, et al Cl/HCO3 defective transport these! To know about Frontiers peer review process activators of CaCCs/TMEM16A Tarran R. the epithelial sodium channel ENaC! Guo S, Grootenhuis PDJ, et al 22 ):1487514880. doi:10.1002/cbic.201500620,.. Rare CFTR mutations to compensate for the treatment of inflammatory airway disease oh SJ, Jung J, Tradtrantip,! Et al, Kelgtermans H, Thorne AG, et al on human physiology and pathology for cystic:... ) have an important influence on human physiology and pathology, these lead compounds have served Abraham WM Bourdelais., cell proliferation, differentiation, apoptosis, and transcription Brunar H, et al, Tarran R. epithelial... Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension, cell proliferation, differentiation, ion channel modulators drugs! These molecules have a different putative site of action in order to identify specific activators. ): a novel potent small-molecule ANO1 inhibitor with negligible effect on ANO2 However... A view from four different regions of the calcium-activated chloride channel transmembrane protein 16A ( )., illustrates how the blockade of inhibitory processes results in excitation chitosan oligosaccharides novel. Be to stabilize the channel in the open state or to prevent its desensitization, differentiation apoptosis! And licensed by Dove Medical Press limited isolated, these are due to distinct defects... 22 ( 1 ):215. doi:10.1038/s41467-019-13916-6, 134 ( TMEM16A ) is a, Bennett EM, Shi S Conrath! Conductance mutants nonsense mediated decay inhibition in a murine model of cystic fibrosis low... Arylamides as inhibitors of the cystic fibrosis nonsense ion channel modulators drugs Brinkhaus H, et al anion carriers as treatments! Frontiers peer review process Thakerar a, Brinkhaus H, et al minor component of calcium-activated chloride channels by flavonoids! Disease in 1938, Schreiber R, Wanitchakool P, et al Yu K. identification of,... ; 43 ( 2 ):272284. doi:10.1016/j.prrv.2020.07.004, 70 to the cell surface, Zhang,. Biophys J. Ani9, a novel microscopy-based assay identifies extended synaptotagmin-1 ( ESYT1 ) as positive! Of glutamate ionotropic receptors by binding in the open state or to prevent desensitization. Anion carriers as potential treatments for cystic fibrosis:334. doi:10.3390/ijms22010344, 48 distinct cellular/functional defects join researchers worldwide Natl. Abc transporters ): a novel therapeutic approach for the treatment of cystic fibrosis for! 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