| 1. |
- Huber, Vincent J., et al.
(author)
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Aquaporins : Chemical inhibition by small molecules
- 2016
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In: Aquaporins in Health and Disease : New Molecular Targets for Drug Discovery - New Molecular Targets for Drug Discovery. - 9781498707831 - 9781498707848 ; , s. 249-271
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Book chapter (peer-reviewed)abstract
- The human genome encodes 13 aquaporin isoforms with characteristic substrate specificity that are expressed at specific locations throughout the body. Of these isoforms, AQPs 1-4 serve important functions in renal water reabsorption. Consequently, specific AQP inhibitors have been proposed as 'aquaretics', a new class of drugs suitable to induce diuresis without concomitant salt wasting. Furthermore, animal experiments suggested that AQP4 inhibitors could be useful to treat some forms of brain edema. Other proposed applications for AQP inhibitors involve amongst others treatment of diabetes, inflammatory skin diseases and cancer. However, few of these putative applications have been critically evaluated against current forms of therapy. Furthermore, development of AQP inhibitors remains difficult and despite numerous efforts during at least the last 15 years very few AQP inhibitors have been described. Moreover, none of the hitherto described substances have been developed to a level where meaningful verification of proposed AQP drug targets in preclinical or clinical settings was possible. Nonetheless, encouraging progress towards development of such substances has been made during recent years. Novel cell-based assays facilitate high throughput screening of chemical compound libraries for hit discovery. AQP 3D structures have been solved for 10 isoforms, which can support rapidly evolving computational hit discovery methods, as well as hit to lead programs. In this chapter, we will provide a critical review of current evidence supporting relevance of AQPs as drug targets, describe current methods for AQP inhibitor discovery and will try to highlight challenges that remain before successful AQP inhibitor development.
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| 2. |
- Nyblom, Maria, et al.
(author)
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Regulation of eukaryotic aquaporins
- 2016
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In: Aquaporins in Health and Disease : New Molecular Targets for Drug Discovery - New Molecular Targets for Drug Discovery. - 9781498707831 - 9781498707848 ; , s. 53-76
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Book chapter (peer-reviewed)abstract
- Membrane-bound water channels known as aquaporins (AQPs) facilitate water transport across biological membranes along osmotic gradients. Since all living cells depend on their ability to maintain water homeostasis, this must be tightly regulated. In eukaryotes, this is achieved by gating, which involves a conformational change of the protein, thereby physically blocking water transport, or by trafficking in which AQPs are shuttled between intracellular storage sites and the plasma membrane. Gating is common amongst plant AQPs in response to environmental stress and has been shown to be triggered by phosphorylation, pH and binding of divalent cations. Gating has been demonstrated for yeast AQPs for which it is believed to confer protection against osmotic shock and rapid freezing. In mammals, AQP regulation is mainly achieved through trafficking. Thirteen AQPs have been identified in humans, the majority of which are regulated by trafficking in response to a wide range of stimuli. The far best characterized trafficking mechanism is that of AQP2 in the kidney collecting duct where it plays a key role in urine concentration. AQP2 trafficking is controlled by the pituitary hormone vasopressin that stimulates phosphorylation of the AQP2 C-terminus, triggering translocation of AQP2 from intracellular storage vesicles to the apical membrane. Defective trafficking of human AQPs can lead to several disease states, for example nephrogenic diabetes insipidus (AQP2) and Sjögren's syndrome (AQP5). In this chapter, we give an overview of what is known about the regulation of eukaryotic AQPs, focusing particularly on structure-function relationships. We discuss the physiological role of AQP regulation, specific regulatory mechanisms and reoccurring themes in both gating and trafficking.
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