Skip to main content
SpringerLink
Log in

Aquaporin-Targeted Therapeutics: State-of-the-Field

  • Chapter
  • First Online:
Aquaporins

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 969))

Abstract

Drugs targeting aquaporins have broad potential clinical applications, including cancer, obesity, edema, glaucoma, skin diseases and others. The astrocyte water channel aquaporin-4 is a particularly compelling target because of its role of brain water movement, neuroexcitation and glia scarring, and because it is the target of pathogenic autoantibodies in the neuroinflammatory demyelinating disease neuromyelitis optica . There has been considerable interest in the identification of small molecule inhibitors of aquaporins, with various candidates emerging from testing of known ion transport inhibitors, as well as compound screening and computational chemistry. However, in general, the activity of reported aquaporin inhibitors has not been confirmed on retesting, which may be due to technical problems in water transport assays used in the original identification studies, and the challenges in modulating the activity of small, compact, pore-containing membrane proteins. We review here the state of the field of aquaporin-modulating small molecules and biologics, and the challenges and opportunities in moving forward.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alam J, Koh JH, Kim N, Kwok SK, Park SH, Song YW, Park K, Choi Y (2016) Detection of autoantibodies against aquaporin-5 in the sera of patients with primary Sjögren's syndrome. Immunol Res 64:849–856

    Google Scholar 

  2. Baum BJ, Alevizos I, Zheng C, Cotrim AP, Liu S, McCullagh L, Goldsmith CM, Burbelo PD, Citrin DE, Mitchell JB, Nottingham LK, Rudy SF, Van Waes C, Whatley MA, Brahim JS, Chiorini JA, Danielides S, Turner RJ, Patronas NJ, Chen CC, Nikolov NP, Illei GG (2012) Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction. Proc Natl Acad Sci U S A 109:19403–19407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Baumgart F, Rossi A, Verkman AS (2012) Light inactivation of water transport and protein-protein interactions of aquaporin-Killer Red chimera. J Gen Physiol 139:83–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Beitz E, Golldack A, Rothert M, von Bülow J (2015) Challenges and achievements in the therapeutic modulation of aquaporin functionality. Pharmacol Ther 155:22–35

    Article  CAS  PubMed  Google Scholar 

  5. Brooks HL, Regan JW, Yool AJ (2000) Inhibition of aquaporin-1 water permeability by tetraethylammonium: involvement of the loop E pore region. Mol Pharmacol 57:1021–1026

    CAS  PubMed  Google Scholar 

  6. Esteva-Font C, Jin BJ, Lee S, Phuan PW, Anderson MO, Verkman AS (2016) Experimental evaluation of proposed small-molecule inhibitors of water channel aquaporin-1. Mol Pharmacol 89:686–693

    Google Scholar 

  7. Esteva-Font C, Jin BJ, Verkman AS (2014) Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice. FASEB J 28:1446–1453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Frigeri A, Nicchia GP, Svelto M (2007) Aquaporins as targets for drug discovery. Curr Pharm Des 13:2421–2427

    Article  CAS  PubMed  Google Scholar 

  9. Hara-Chikuma M, Satooka M, Watanabe S, Honda T, Miycahi Y, Watanabe T, Verkman AS 2015 Aquaporin-3-mediated hydrogen peroxide transport required for NF-κB signaling in keratinocytes and development of psoriasis. Nat Commun 6:7454

    Google Scholar 

  10. Hara-Chikuma M, Verkman AS (2008) Prevention of skin tumorigenesis and impairment of epidermal cell proliferation by targeted aquaporin-3 gene disruption. Mol Cell Biol 28:328–332

    Article  Google Scholar 

  11. Hinson SR, Romero MF, Popescu BF, Lucchinetti CF, Fryer JP, Wolburg H, Fallier-Becker P, Noell S, Lennon VA (2012) Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc Natl Acad Sci U S A 109:1245–1250

    Article  CAS  PubMed  Google Scholar 

  12. Huber VJ, Tsujita M, Kwee IL, Nakada T (2009) Inhibition of aquaporin 4 by antiepileptic drugs. Bioorg Med Chem 17:418–424

    Article  CAS  PubMed  Google Scholar 

  13. Huber VJ, Tsujita M, Nakada T (2009) Identification of Aquaporin 4 inhibitors using in vitro and in silico methods. Bioorg Med Chem 17:411–417

    Article  CAS  PubMed  Google Scholar 

  14. Jeyaseelan K, Sepramaniam S, Armugam A, Wintour EM (2006) Aquaporins: a promising target for drug development. Expert Opin Ther Targets 10:889–909

    Article  CAS  PubMed  Google Scholar 

  15. Jin BJ, Esteva-Font C, Verkman AS (2015) Droplet-based microfluidic platform for measurement of rapid erythrocyte water transport. Lab Chip 15:3380–3390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jin BJ, Battula S, Zachos N, Kovbasnjuk O, Fawlke-Abel J, In J, Donowitz M, Verkman AS (2014) Microfluidics platform for measurement of volume changes in immobilized intestinal enteroids. Biomicrofluidics 8:024106

    Article  PubMed  PubMed Central  Google Scholar 

  17. Landegren N, Pourmousa Lindberg M, Skov J, Hallgren Å, Eriksson D, Lisberg Toft-Bertelsen T, MacAulay N, Hagforsen E, Räisänen-Sokolowski A, Saha H, Nilsson T, Nordmark G, Ohlsson S, Gustafsson J, Husebye ES, Larsson E, Anderson MS, Perheentupa J, Rorsman F, Fenton RA, Kämpe O (2016) Autoantibodies targeting a collecting duct-specific water channel in tubulointerstitial nephritis. J Am Soc Nephrol 27:3220–3228

    Google Scholar 

  18. Levin MH, de la Fuente R, Verkman AS (2007) Urearetics: a small molecule screen yields nanomolar potency inhibitors of urea transporter UT-B. FASEB J 21:551–563

    Article  CAS  PubMed  Google Scholar 

  19. Ma T, Song Y, Yang B, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS (2000) Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels. Proc Natl Acad Sci U S A 97:4386–4391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Macey RI, Farmer RE (1970) Inhibition of water and solute permeability in human red cells. Biochim Biophys Acta 211:104–106

    Article  CAS  PubMed  Google Scholar 

  21. Mangiatordi GF, Alberga D, Sirgusa L, Goracci L, Lattandi G, Nicolotti O. Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction field. 2015; 1848:1462–1471.

    Google Scholar 

  22. Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen A, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163

    Article  CAS  PubMed  Google Scholar 

  23. Marrone J, Soria LR, Danielli M, Lehmann GL, Larocca MC, Marinelli RA (2016) in press Hepatic gene transfer of human aquaporin-1 improves bile salt secretory failure in rats with estrogen-induced cholestasis. Hepatology 64:534–548

    Google Scholar 

  24. Martins AP, Ciancetta A, de Almeida A, Marrone A, Re N, Soveral G, Casini A (2013) Aquaporin inhibition by gold(III) compounds: new insights. ChemMedChem 8:1086–1092

    Article  CAS  PubMed  Google Scholar 

  25. Migliati E, Meurice N, DuBois P, Fang JS, Somasekharan S, Beckett E, Flynn G, Yool A (2009) Inhibition of aquaporin-1 and aquaporin-4 water permeability by a derivative of the loop diuretic bumetanide acting at an internal pore-occluding binding site. Mol Pharmacol 76:105–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mola MG, Nicchia GP, Svelto M, Spray DC, Frigeri A (2009) Automated cell-based assay for screening of aquaporin inhibitors. Anal Chem 81:8219–8229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Oliva AA, Kang Y, Truettner JS, Sanchez-Molano J, Furones C, Yool AJ, Atkins CM (2011) Fluid-percussion brain injury induces changes in aquaporin channel expression. Neurobiologia 180:272–279

    CAS  Google Scholar 

  28. Papadopoulos MC, Bennett JL, Verkman AS (2014) Treatment of neuromyelitis optica: state-of-the-art and emerging therapies. Nat Rev Neurosci 10:493–506

    CAS  Google Scholar 

  29. Patil RV, Xu S, van Hoek AN, Rusinko A, Feng Z, May J, Hellberg M, Sharif NA, Wax MB, Irigoyen M, Carr G, Brittain T, Brown P, Colbert D, Kumari S, Varadaraj K, Mitra AK (2016) Rapid identification of novel inhibitors of the human aquaporin-1 water channel. Chem Biol Drug Des 87:794–805

    Google Scholar 

  30. Rossi A, Ratelade J, Papadopoulos MC, Bennett JL, Verkman AS (2012) Neuromyelitis optica IgG does not alter aquaporin-4 water permeability, plasma membrane M1/M23 isoform content, or supramolecular assembly. Glia 60:2027–2039

    Article  PubMed  PubMed Central  Google Scholar 

  31. Saadoun S, Papadopoulos MC, Hara-Chikuma M, Verkman AS (2005) Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption. Nature 434:786–792

    Article  CAS  PubMed  Google Scholar 

  32. Schnermann J, Chou CL, Ma T, Traynor T, Knepper MA, Verkman AS (1998) Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice. Proc Natl Acad Sci U S A 95:9660–9664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Seeliger D, Zapater C, Krenc D, Haddoub R, Flitsch S, Beitz E, Cerda J, de Groot BL (2013) Discovery of novel human aquaporin-1 blockers. ACS Chem Biol 8:249–256

    Article  CAS  PubMed  Google Scholar 

  34. Søgaard R, Zeuthen T (2008) Test of blockers of AQP1 water permeability by a high-resolution method: no effects of tetraethylammonium ions or acetazolamide. Pflugers Arch 456:285–292

    Article  PubMed  Google Scholar 

  35. Solenov E, Watanabe H, Manley GT, Verkman AS (2004) Sevenfold-reduced osmotic water permeability in primary astrocyte cultures from AQP-4-deficient mice, measured by a fluorescence quenching method. Am J Phys 286:C426–C432

    Article  CAS  Google Scholar 

  36. To J, Yeo CY, Soon CH, Torres J (1850) A generic high-throughput assay to detect aquaporin functional mutants: Potential application to discovery of aquaporin inhibitors. Biochim Biophys Acta 2015:1869–1876

    Google Scholar 

  37. Tradtrantip L, Zhang H, Saadoun S, Phuan PW, Lam C, Papadopoulos MC, Bennett JL, Verkman AS (2012) Ann Neurol 71:314–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tradtrantip L, Zhang H, Anderson MO, Saadoun S, Phuan PW, Papadopoulos MC, Bennett JL, Verkman AS (2012) Small molecule inhibitors of NMO-IgG binding to aquaporin-4 reduce astrocyte cytotoxicity in neuromyelitis optica. FASEB J 26:2197–2208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Verkman AS (2012) Aquaporins in clinical medicine. Annu Rev Med 63:303–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Verkman AS, Anderson MO, Papadopoulos MC (2014) Aquaporins: important but elusive drug targets. Nat Rev Drug Discov 13:259–277

    Google Scholar 

  41. Wacker SJ, Aponte-Santamaria C, Kjellbom P, Nielsen S, De Groot BL, Rutzler M (2013) The identification of novel, high affinity AQP9 inhibitors in an intracellular binding site. Mol Membr Biol 30:246–260

    Article  CAS  PubMed  Google Scholar 

  42. Wang F, Feng XC, Li YM, Yang H, Ma TH (2006) Aquaporins as potential drug targets. Acta Pharmacol Sin 27:395–401

    Article  CAS  PubMed  Google Scholar 

  43. Yamaguchi T, Iwata Y, Miura S, Kawada K (2012) Reinvestigation of drugs and chemicals as aquaporin-1 inhibitors using pressure-induced hemolysis in human erythrocytes. Biol Pharm Bull 35:2088–2091

    Article  CAS  PubMed  Google Scholar 

  44. Yang B, Kim JK, Verkman AS (2006) Comparative efficacy of HgCl2 with candidate aquaporin-1 inhibitors DMSO, gold, TEA+ and acetazolamide. FEBS Lett 580:6679–6684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang B, Zhang H, Verkman AS (2008) Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides. Bioorg Med Chem 16:7489–7493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yool AJ, Morelle J, Cnops Y, Verbavatz JM, Campbell EM, Beckett EA, Booker GW, Flynn G, Devuyst O (2013) AqF026 is a pharmacologic agonist of the water channel aquaporin-1. J Am Soc Nephrol 24:1045–1052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhang D, Vetrivel L, Verkman AS (2002) Aquaporin deletion in mice reduces intraocular pressure and aqueous fluid production. J Gen Physiol. 119:561–569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang R, van Hoek AN, Biwersi J, Verkman AS (1993) A point mutation at cysteine 189 blocks the water permeability of rat kidney water channel CHIP28k. Biochemist 32:2938–2941

    Article  CAS  Google Scholar 

  49. Zhang H, Verkman AS (2010) Aquaporin-1 tunes pain perception by interaction with Nav1.8 Na+ channels in dorsal root ganglion neurons. J Biol Chem 285:5896–5906

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants DK101373, DK35124, DK72517, EB00415, EY13574 and DK99803 from the National Institutes of Health, and grants from the Guthy-Jackson Charitable Foundation and the Cystic Fibrosis Foundation.

Author information

Authors and Affiliations

  1. Departments of Medicine and Physiology, University of California, San Francisco, CA, 94143-0521, USA

    Lukmanee Tradtrantip Ph.D., Bjung-Ju Jin Ph.D., Xiaoming Yao M.D. & Alan S. Verkman M.D., Ph.D.

  2. Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA, 94132-4136, USA

    Marc O. Anderson Ph.D.

Authors
  1. Lukmanee Tradtrantip Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bjung-Ju Jin Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoming Yao M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marc O. Anderson Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alan S. Verkman M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan S. Verkman M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China

    Baoxue Yang

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Tradtrantip, L., Jin, BJ., Yao, X., Anderson, M.O., Verkman, A.S. (2017). Aquaporin-Targeted Therapeutics: State-of-the-Field. In: Yang, B. (eds) Aquaporins. Advances in Experimental Medicine and Biology, vol 969. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-1057-0_16

Download citation

Publish with us

Policies and ethics

Search

Navigation