title: Aquaporin-Targeted Therapeutics: State-of-the-Field.
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.
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA, 94143-0521, USA.
authors.forename: Lukmanee
authors.initials: L
authors.lastname: Tradtrantip
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA, 94143-0521, USA.
authors.forename: Bjung-Ju
authors.initials: BJ
authors.lastname: Jin
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA, 94143-0521, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA, 94132-4136, USA.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Anderson
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA, 94143-0521, USA. alan.verkman@ucsf.edu.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D001929:Brain Edema / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D058990:Molecular Targeted Therapy; D009471:Neuromyelitis Optica / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009994:Osmolar Concentration; D009997:Osmotic Pressure; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018170:Sumatriptan / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology; D014867:Water / Q000378:metabolism*
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D020033:Protein Isoforms; D013830:Thiadiazoles; D014230:Triazoles; D014363:Tryptamines; D014867:Water; C093622:rizatriptan; D018170:Sumatriptan
keywords: AQP; Brain edema; Drug discovery; Neuromyelitis optica; Water channel