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Aquaporins: important but elusive drug targets

Nature Reviews Drug Discovery volume 13, pages 259–277 (2014)Cite this article

Subjects

Key Points

  • Aquaporins (AQPs) are water channel proteins that are expressed in the plasma membranes of cells. They are involved in many physiological functions, including renal water balance, epithelial fluid secretion, cell migration, brain oedema and metabolism in adipocytes.

  • Aquaporinopathies include nephrogenic diabetes insipidus (which is caused by a loss-of-function mutation in AQP2) and neuromyelitis optica (which is caused by the development of AQP4-targeted autoantibodies).

  • Modulators of AQP function are predicted to have broad clinical indications in oedema, cancer, obesity, brain injury, glaucoma, epilepsy and inflammation.

  • The identification of useful small-molecule AQP inhibitors has been slow, in part because of technical challenges in assaying the water-transporting function of AQPs and challenges associated with targeting the compact, pore-containing AQP molecule.

Abstract

The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators.

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Figure 1: Structure of aquaporins.
Figure 2: Tissue distribution of mammalian aquaporins.
Figure 3: Major physiological functions of aquaporins.
Figure 4: Assays of aquaporin-mediated water transport.
Figure 5: Putative aquaporin-targeted small-molecule modulators.
Figure 6: AQP4-targeted therapies for neuromyelitis optica and nephrogenic diabetes insipidus.

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Acknowledgements

The authors' research is funded by the US National Institutes of Health (A.S.V. and M.O.A.), the Guthy-Jackson Charitable Foundation (A.S.V. and M.C.P.) and the Cystic Fibrosis Foundation (A.S.V.).

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Authors and Affiliations

  1. Departments of Medicine and Physiology, 1246 Health Sciences East Tower, University of California, San Francisco, 94143–0521, California, USA

    Alan S. Verkman

  2. Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave, San Francisco, 94132, California, USA

    Marc O. Anderson

  3. Academic Neurosurgery Unit, Room 1.122 Jenner Wing, St George's, University of London, Tooting, London, SW17 0RE, UK

    Marios C. Papadopoulos

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Correspondence to Alan S. Verkman.

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Competing interests

A.S.V. is a named co-inventor on several aquaporin (AQP)-related patents, including a patent on aquaporin monoclonal antibodies to treat neuromyelitis optica (NMO). Patent rights are assigned to the University of California, San Francisco (UCSF).

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Glossary

Aquaglyceroporin

A class of the aquaporins (AQP3, AQP7 and AQP9) that transport glycerol in addition to water.

Virtual screening

A computational technique that is used to identify small-molecule modulators of a drug target. This is typically conducted in a structure-based manner (using protein–ligand docking) or in a ligand-based manner (using similarity searching or through the use of pharmacophore models).

Molecular dynamics simulations

Computational methods that simulate the physical motion of atoms and molecules. When applied to biomolecules, the results are typically trajectories of the atoms of the protein, solvent, ions, bound ligands and so on, over timescales that range from nanoseconds to microseconds.

Grotthuss-type 'proton-wire' mechanism

A hypothesis for proton movement in bulk water, where a proton can 'hop' along a continuous line of water molecules in a hydrogen-bonded network, with the resultant reorientation of water molecules after the transfer has occurred.

Free-energy profiles

A term that is used to describe the estimated energetics of a molecule passing through the span of a channel protein; it is usually calculated by molecular dynamics simulations.

Salt transport-blocking diuretics

Drugs that inhibit the absorption of Na+, K+ and Cl−ions in the kidney and therefore secondarily inhibit water absorption. For example, amiloride inhibits the epithelial sodium channel in the distal tubule, and furosemide inhibits the Na+/K+/2Cl− symporter in the thick ascending limb of the loop of Henle.

Aquaretic response

The urinary elimination of water without electrolyte loss (as opposed to a diuretic response in which urinary elimination of water is secondary to the elimination of salt).

Astrocyte end-feet

Astrocyte processes that surround microvascular endothelial cells in the central nervous system.

Vasogenic oedema

Oedema in the central nervous system where water accumulates in extracellular spaces.

Cortical spreading depression

A wave of depolarization that spreads in the brain and is followed by the suppression of brain activity.

Glial scar

A scar in the central nervous system that is formed in response to damage and involves reactive astrocytes and microglia.

Density functional theory calculations

A computational method that uses quantum-mechanical theory to model the energy and chemical structure of molecules.

Infiltrating tumour cells

Tumour cells that spread into normal tissue such that there is no clear border between the tumour and the normal tissue.

Stratum corneum

The outermost layer of the epidermis that is composed of dead cells (that is, keratinocytes).

Lens fibres

Long, thin transparent cells that form the bulk of the lens, arranged in concentric layers.

Gap junction channels

Intercellular channels composed of connexin proteins that allow the passage of small molecules (typically <1 kDa) between cells.

Palmoplantar keratoderma

A disease that is characterized by abnormal thickening of the skin on the palms of hands and soles of feet.

Ussing chamber

An apparatus in which a cell layer separates two solution compartments; it is used to measure ion transport.

Stopped-flow measurements

Assays that are carried out using an apparatus in which two solutions are mixed together rapidly (in <1 millisecond) and have an optical read-out.

IC50 value

The concentration of a compound that produces 50% inhibition of a target function.

Parotiditis

Inflammation of the parotid salivary gland.

Therapeutic apheresis

The passage of blood through a filtering apparatus to remove or inactivate a pathogenic substance.

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Verkman, A., Anderson, M. & Papadopoulos, M. Aquaporins: important but elusive drug targets. Nat Rev Drug Discov 13, 259–277 (2014). https://doi.org/10.1038/nrd4226

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