Challenges and achievements in the therapeutic modulation of aquaporin functionality.
Aquaporin (AQP) water and solute channels have basic physiological functions throughout the human body. AQP-facilitated water permeability across cell membranes is required for rapid reabsorption of water from pre-urine in the kidneys and for sustained near isosmolar water fluxes e.g. in the brain, eyes, inner ear, and lungs. Cellular water permeability is further connected to cell motility. AQPs of the aquaglyceroporin subfamily are necessary for lipid degradation in adipocytes and glycerol uptake into the liver, as well as for skin moistening. Modulation of AQP function is desirable in several pathophysiological situations, such as nephrogenic diabetes insipidus, Sjögren's syndrome, Menière's disease, heart failure, or tumors to name a few. Attempts to design or to find effective small molecule AQP inhibitors have yielded only a few hits. Challenges reside in the high copy number of AQP proteins in the cell membranes, and spatial restrictions in the protein structure. This review gives an overview on selected physiological and pathophysiological conditions in which modulation of AQP functions appears beneficial and discusses first achievements in the search of drug-like AQP inhibitors.
Pharmaceutical and Medicinal Chemistry, University of Kiel, Germany. Electronic address: ebeitz@pharmazie.uni-kiel.de.
Eric
E
Beitz
Pharmaceutical and Medicinal Chemistry, University of Kiel, Germany.
André
A
Golldack
Pharmaceutical and Medicinal Chemistry, University of Kiel, Germany.
Monja
M
Rothert
Pharmaceutical and Medicinal Chemistry, University of Kiel, Germany.
Julia
J
von Bülow
D000818:Animals; D020346:Aquaporins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001681:Biological Assay; D006801:Humans
D020346:Aquaporins
Aquaporin; Drug development; Glycerol; Inhibition; Volume regulation; Water