Artificial transmembrane ion transporters as potential therapeutics

Artificial transmembrane ion transporters are attractive in the context of drug discovery since, principle, they may be used as novel therapeutics by promoting apoptosis (programmed cell death), interfering with autophagic processes, or inducing an antibiotic response via disrupting cellular homeostasis dissipating intracellular pH gradients. Considerable effort has been devoted into design artificial selective recognition and transport. However, only limited progress made terms translating fundamental research involving transport mechanisms systems that function vitro. In this review, we summarize recent area a focus on their application potential therapeutics. The associated discussion accomplishments remaining challenges is designed to hasten day when translated bona fide clinical benefits. Various transporters, through mobile carrier channel mechanisms, have developed past decade. With aid structural manipulation employing either discrete chemical entities self-assembled nanostructures, achieving key ions. ability perturb disrupt makes interest might see use cancer treatments antibacterial agents. transporter summarized emphasis applications anticancer applications. examples chosen for highlights meant illustrative themes synthetic rather than comprehensive. Nevertheless, it anticipated review will provide useful entry point general reader set stage further area. Cellular membranes serve barriers exchange most substrates out cells. solutes between cells extracellular milieu crucial maintaining normal operation biological systems.1Szostak J.W. Bartel D.P. Luisi P.L. Synthesizing life.Nature. 2001; 409: 387-390Google Scholar, 2Dubyak G.R. Ion homeostasis, channels, transporters: update mechanisms.Adv. Physiol. Educ. 2004; 28: 143-154Google 3Bröer S. Amino acid across mammalian intestinal renal epithelia.Physiol. Rev. 2008; 88: 249-286Google Scholar Small neutral compounds, such water carbon dioxide, can cross phospholipid relatively easily diffusion. On other hand, charged species, including physiologically important anions cations, relies assistance proteins carriers channels.4Gamper N. Shapiro M.S. Regulation membrane phosphoinositides.Nat. Neurosci. 2007; 8: 921-934Google 5Wang X. Zhang Dong X.P. Samie M. Li Cheng Goschka A. Shen D. Zhou Y. Harlow J. et al.TPC phosphoinositide-activated sodium-selective channels endosomes lysosomes.Cell. 2012; 151: 372-383Google 6Guo Zeng W. Chen Q. Lee C. L. Yang Cang Ren Jiang Structure voltage-gated two-pore TPC1 from Arabidopsis thaliana.Nature. 2016; 531: 196-201Google healthy cells, cooperative feedback various serves maintain precisely gradients and, result, desired concentrations processes.7Sheppard D.N. Rich Ostedgaard L.S. Gregory R.J. Smith A.E. Welsh M.J. Mutations CFTR mild-disease-form Cl- altered pore properties.Nature. 1993; 362: 160-164Google 8Choi J.Y. Muallem Kiselyov K. M.G. Thomas P.J. Aberrant CFTR-dependent HCO3? mutations cystic fibrosis.Nature. 410: 94-97Google 9Vaughan-Jones R.D. Spitzer K.W. Swietach P. Intracellular regulation heart.J. Mol. Cell. Cardiol. 2009; 46: 318-331Google Failure typically manifest severe pathological consequences. For instance, dysfunction Cl? fibrosis, disease correlated higher-than-normal chloride anion concentrations.10Gadsby D.C. Vergani Csanády ABC protein turned whose failure causes 2006; 440: 477-483Google fibrosis disorders traced disruptions could controlled treating patients functioning channels. availability, poor stability, complexity natural so far precluded these practical simpler molecular mimic salient properties means overcome limitations (so-called replacement therapy).11Ghadiri M.R. Granja J.R. Buehler L.K. self-assembling peptide nanotubes.Nature. 1994; 369: 301-304Google 12Sakai Matile Synthetic channels.Langmuir. 2013; 29: 9031-9040Google 13Gokel G.W. Negin channels: pores applications.Acc. Chem. Res. 2824-2833Google 14Fyles T.M. bilayer membranes.Chem. Soc. 36: 335-347Google 15Barboiu Gilles From bioassisted biomimetic systems.Acc. 2814-2823Google 16Montenegro Ghadiri models based cyclic nanotubes.Acc. 2955-2965Google Appropriate allow adaptable achieved range ionic targets, species chloride, potassium, sodium. context, both unimers) nanostructures subject study.17Carmichael V.E. Dutton Fyles James T.D. Swan J.A. Zojaji Biomimetic transport: functional model unimolecular channel.J. Am. 1989; 111: 767-769Google 18Baumeister B. Sakai Giant formed self-assembled, cationic rigid-rod ?-barrels.Angew. Int. Ed. 2000; 39: 1955-1958Google 19Gokel Murillo O. organic channels.Acc. 1996; 425-432Google 20Li Wu Y.D. ?-Aminoxy acids: new possibilities foldamers receptors 41: 1428-1438Google 21Fyles How do amphiphiles form ion-conducting membranes? Lessons linear oligoesters.Acc. 2847-2855Google 22Sisson A.L. Shah Bhosale (2004-2005).Chem. 35: 1269-1286Google addition targeting transport-related disorders, (collectively referred transporters) show promise perturbing homeostasis.23Davis J.T. Gale P.A. Quesada R. Advances supramolecular medicinal chemistry.Chem. 2020; 49: 6056-6086Google construction (channels carriers) A treatment opportunities afforded also included. Over decades, enormous understanding cancer. remains second largest cause death worldwide. Currently, systemic treatments, drugs (chemotherapy, hormone, therapies), modalities choice many instances. indiscriminate destruction toxicity conventional chemotherapeutic drugs, well development multi-drug resistance, incentive seek action. which induce programmed death) changing one alternative approach.24Hosogi Kusuzaki Inui T. Wang Marunaka Cytosolic factor lysosomal acidification autophagy human gastric cell.J. Med. 2014; 18: 1124-1133Google 25Busschaert Park S.H. Baek K.H. Choi Y.P. Howe E.N.W. Hiscock Karagiannidis L.E. Marques I. Félix V. al.A disrupts induces concentrations.Nat. 2017; 9: 667-675Google 26Smith B.A. Daschbach M.M. Gammon S.T. Xiao Chapman S.E. Hudson al.In vivo mediated channels.Chem. Commun. 2011; 47: 7977-7979Google 27Park Hyun L.J. Hwang Vargas-Zuñiga G. Busschaert Sessler J.L. Shin Determinants ion-transporter death.Chem. 2019; 5: 2079-2098Google 28Rodilla A.M. Korrodi-Gregório Hernando E. Manuel-Manresa Pérez-Tomás Soto-Cerrato tambjamine analogues mitochondrial swelling leading blockade necrotic lung cancer.Biochem. Pharmacol. 126: 23-33Google 29Kim D.H. Rozhkova E.A. Ulasov I.V. Bader S.D. Rajh Lesniak Novosad Biofunctionalized magnetic-vortex microdiscs targeted cancer-cell destruction.Nat. Mater. 2010; 165-171Google 30Alfonso Biological activity ionophores: prospective drugs?.Chem. Sci. 4: 3009-3019Google Moreover, possible combining therapeutic modalities, resistance effectively overcome.31Li H. Valkenier Thorne A.G. Dias C.M. Cooper Kieffer Sheppard Davis A.P. Anion fibrosis: additivity channel-targeting drugs.Chem. 10: 9663-9672Google It appreciate benefits not Bacteria targets. As result imbalance bacterial membranes, several shown motifs years.32Leevy W.M. Donato G.M. Ferdani Goldman W.E. Schlesinger P.H. Gokel hydraphile appropriate length kill Escherichia coli.J. 2002; 124: 9022-9023Google Scholar,33Brea Reiriz Towards bionanomaterials nanotubes.Chem. 1448-1456Google polyether ionophores, complex products cations often display antimicrobial activity, finding inspired synthesis agents.34Kevin II, D.A. Meujo Hamann M.T. Polyether broad-spectrum promising biologically active molecules control drug-resistant bacteria parasites.Expert Opin. Drug Discov. 109-146Google Since variety reported date, classified according type ions involved, particular being given This reflects physiological importance but fact target work date. Additionally, represent selection literature studied extensively systems. To readers introductory guideline field, brief summary section. term applies shuttles doing so, brings about translocation (Figure 1). contrast, scaffolds mediate bilayers without undergoing appreciable motion disturbing lipid supra-structures. include Unimolecular macrocyclic long enough insert guides An advantage reflecting comprise single remain intact inside bilayers. difficult time consuming. Therefore, majority date created situ self-assembly monomers within constructing stable structures binding sites rational smaller building blocks challenge. differentiate carrier-type transporter, black (BLM) experiments planar performed 2A).35Matile characterization pores.in: Schalley C.A. Analytical Methods Supramolecular Chemistry. Second Edition. Wiley-VCH, Weinheim, Germany2012: 711-742Google Dynamic “open-closed” conductance generally taken evidence formation 2B). some parameters inferred studies, g, lifetime ?1, open probability Po. so-called Hill plots another tool distinguish carrier- channel-based mechanisms.36Litvinchuk Bollot Mareda Som Ronan Perrottet Thermodynamic kinetic stability multifunctional ?-barrel pores: catalysis.J. 10067-10075Google slope plot equal coefficient interactions agent question under study. greater 1.0 indication there synergistic concentration dependence (channel mechanism), whereas less indicates competitive (carrier mechanism) 3A). These limiting regimes interpreted respectively. appreciated analyses fully developed, caution must exercised drawing concrete mechanistic conclusions.Figure 3(A) Typical transporters. Reprinted permission Sakai,35Matile copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.Show full caption(B) Standard configuration HPTS (8-hydroxypyrene-1,3,6-trisulfonic acid) assay. al.,37Wu assays insights.Acc. 2018; 51: 1870-1879Google 2018 American Chemical Society.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (B) Society. involved mediating molecule termed uniporter, process uniport. Transporters move two same direction called symporters. If moved opposite directions bilayer, antiport. movement specific ionophores. action moving results net change charge, described electrogenic; if no electroneutral. primary method characterize putative cell-free conditions liposomal assay.37Wu general, fluorescence spectroscopy monitor fluorophore-containing large unilamellar vesicles (LUVs). Depending setup fluorescent probes employed, insights influx efflux types Often, LUVs prepared 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) then encapsulated pH-sensitive ratiometric dye 8-hydroxypyrene-1,3,6-trisulfonic (HPTS) halide-sensitive fluorophore lucigenin 3B). intensities calibrated concentrations, allows optical-based monitoring H+ processes. Other methods changes NMR ion-selective electrodes, assays. test whether compound act its cytosolic needs evaluated. Taking example, matrix monitored using chloride-selective probe, N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE), undergoes quenching presence upon preincubation effective channel, MQAE would expected due increase concentration.38Verkman A.S. Sellers M.C. Chao A.C. Leung Ketcham Synthesis improved chloride-sensitive indicators applications.Anal. Biochem. 178: 355-361Google related strategy involves Fischer rat thyroid epithelial (FRT) express mutant yellow (YFP) sensitively quenched ions.39Jayaraman Haggie Wachter R.M. Remington S.J. Verkman Mechanism green protein-based halide sensor.J. Biol. 275: 6047-6050Google Based level quenching, extent estimated. FRT expressing YFP induced low levels endogenous channels/carriers detected. Thus, engineered tools determining promotes influx. death. effect viability assessed standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay.40Van Meerloo Kaspers G.J. Cloos Cell sensitivity assays: assay.Methods 731: 237-245Google Apoptosis determined mixture fluorescein-labeled annexin V propidium iodide (PI).41Williams D.R. Ko S.K. apoptosis-inducing small binds heat shock 70.Angew. 7466-7469Google give rise positive PI uptake. Because loss hallmark apoptosis, event membrane-potential-sensitive probe JC-1. Cells JC-1 decrease red fluorescence.42Salvioli Ardizzoni Franceschi Cossarizza JC-1, DIOC6(3) rhodamine 123, reliable assess ?? cells: implications studies functionality during apoptosis.FEBS Lett. 1997; 411: 77-82Google observation DNA fragmentation provides additional apoptosis.43Hengartner M.O. biochemistry apoptosis.Nature. 407: 770-776Google electrophoresis, nucleus analysis after staining DNA-binding terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) Taken concert, systematic robust support conclusion apoptosis. Selective regulated plays role Transmembrane essential proliferation appear play was initially noted case potassium suggested cation channels.44Kunzelmann cancer.J. Membr. 2005; 205: 159-173Google over considerable creating help understand functions fact, number promote through-membrane ions, sodium, date.45Benke B.P. Aich Kim K.L. Rohman Hong I.C. E.H. Roh J.H. Iodide-selective shape-persistent cages.J. 139: 7432-7435Google 46Lang Z. F. al.Biomimetic high transporting efficiency helically folded macromolecules.Angew. 55: 9723-9727Google 47Burns Seifert Fertig Howorka DNA-based ligand-controlled cargo membrane.Nat. Nanotechnol. 11: 152-156Google 48Haynes C.J.E. Zhu Chimerel Hernández-Ainsa Riddell I.A. Ronson T.K. al.Blockable Zn10L15 subcomponent self-assembly.Angew. 56: 15388-15392Google Self-assembled subunits noncovalent interactions, hydrogen bonding, ?-? donor-acceptor metal coordination, etc., widely transporters.49Talukdar ?-stack architecture charge-transfer formation.J. 127: 6528-6529Google 50Danial Tran C.M.N. Jolliffe K.A. Perrier Thermal gating thermoresponsive peptide–polymer conjugates.J. 136: 8018-8026Google 51Jung metal–organic polyhedra.Angew. 5755-5757Google cases, classic ion-binding motifs, crown ethers cation- anion-? slides, incorporated transporters.52Pfeifer Reiss Koert U. Crown ether–gramicidin hybrid dehydration-assisted selectivity.Angew. 45: 501-504Google 53Kumpf R.A. Dougherty mechanism selectivity computational cation-pi interactions.Science. 261: 1708-1710Google 54Vargas Jentzsch Hennig anion?? halogen bonds, anion–macrodipole interactions.Acc. 2791-2800Google 55Behera Madhavan Anion-selective cholesterol decorated carriers.J. 12919-12922Google 56Yuan Ye Structurally simple trimesic amides highly 4797-4800Google exploited acyclic hosts, squaramides, pillararenes, calixarenes, cucurbiturils, calixpyrroles.57Busschaert Kirby I.L. Young Coles Horton P.N. Light M.E. al.Squaramides potent transporters.Angew. 4426-4430Google 58Si Xin Z.T. Hou Tubular activities.Acc. 2015; 48: 1612-1619Google 59Kaucher Harrell W.A. G-quadruplex Na+ transporter.J. 128: 38-39Google 60Su Si Directional channel.Angew. 14678-14682Google 61Jeon Y.J. Jon Selvapalam Oh Seo al.Artificial cucurbit[n]uril derivatives carbonyl group fringed portal reminiscent filter K+ channels.J. 15944-15945Google 62Kim D.S. Calix[4]pyrroles: versatile containers transport, recognition, switching functions.Chem. 44: 532-546Google 5–15 mM 110 mM, respectively.63Sonawane N.D. Thiagarajah Chloride measured ratioable indicator: accumulation acidification.J. 277: 5506-5513Google Naturally occurring (Cl?) (e.g., channels) significant roles regulating pH; controlling electrical excitability. circumvent equilibrium critical gradients, cells.64Saha Hossain Saha Lahiri Talukdar Chloride-mediated bis (sulfonamide) anionophores.J. 138: 7558-7567Google cancer, t