Challenges and achievements in the therapeutic modulation of aquaporin functionality

Beitz, Eric; Golldack, André; Rothert, Monja; Bülow, Julia von

doi:10.1016/j.pharmthera.2015.08.002

Cited by 48 publications

(38 citation statements)

References 191 publications

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“…Even if this research area is underdeveloped, two recent reviews by Verkman et al (2014) [13] and Beitz et al (2015) [127] provide an overview on AQP-related disorders and pharmacological intervention in the therapeutic modulation of aquaporin functionality, identifying protein structural and chemical aspects of AQP modulator design. Indeed, the modulation of AQP functions is desirable in other several pathophysiological situations not only in the gut, such as cancer, heart failure, nephrogenic diabetes insipidus, and Sjögren’s syndrome.…”

Section: Discussionmentioning

confidence: 99%

Aquaporins in Health and Disease: An Overview Focusing on the Gut of Different Species

Pelagalli

Squillacioti

Mirabella

et al. 2016

IJMS

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Aquaporins (AQPs) play a pivotal role in gut homeostasis since their distribution and function is modulated both in physiological and in pathophysiological conditions. The transport of water and solutes through gut epithelia is essential for osmoregulation and digestive and absorptive functions. This passage is regulated by different AQP isoforms and characterized by their peculiar distribution in the gastrointestinal tract. To date, AQP localization has been identified in the gut and associated organs of several mammalian species by different techniques (immunohistochemical, western blotting, and RT-PCR). The present review describes the modulation of AQP expression, distribution, and function in gut pathophysiology. At the same time, the comparative description of AQP in animal species sheds light on the full range of AQP functions and the screening of their activity as transport modulators, diagnostic biomarkers, and drug targets. Moreover, the phenotype of knockout mice for several AQPs and their compensatory role and the use of specific AQP inhibitors have been also reviewed. The reported data could be useful to design future research in both basic and clinical fields.

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Section: Discussionmentioning

confidence: 99%

Aquaporins in Health and Disease: An Overview Focusing on the Gut of Different Species

Pelagalli

Squillacioti

Mirabella

et al. 2016

IJMS

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“…Thus, they have been suggested as potential targets for drug development. [3][4][5] Specifically, aquaglyceroporins regulate glycerol content in epidermis, fat and other tissues and appear to be involved in skin hydration, cell proliferation, carcinogenesis and fat metabolism. 1,6 To validate the various roles of AQPs in health and disease, and to develop AQP-targeted therapies, in addition to genetic approaches, the use of selective inhibitors holds great promise.…”

Section: Introductionmentioning

confidence: 99%

The mechanism of aquaporin inhibition by gold compounds elucidated by biophysical and computational methods

et al. 2017

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The inhibition of water and glycerol permeation via human aquaglyceroporin-3 (AQP3) by gold(iii) complexes has been studied by stopped-flow spectroscopy and, for the first time, its mechanism has been described using molecular dynamics (MD), combined with density functional theory (DFT) and electrochemical studies. The obtained MD results showed that the most effective gold-based inhibitor, anchored to Cys40 in AQP3, is able to induce shrinkage of pores preventing glycerol and water permeation. Moreover, the good correlation between the affinity of the Au(iii) complex to Cys binding and AQP3 inhibition effects was highlighted, while no influence of the different oxidative character of the complexes could be observed.

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“…Though there is much speculation about the utility of AQP-targeted therapeutics [4, 8, 14, 40, 42], as well as compelling animal data to support AQP drug development, progress in the field has been disappointing. Reports of AQP inhibition by common ion transport inhibitors, such as loop diuretics and antiepileptics, have confused the literature, as have reports of small molecule AQP inhibitors that could not be confirmed on retesting.…”

Section: 4 Perspective and Future Directionsmentioning

confidence: 99%

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

Tradtrantip

Jin

Yao

et al. 2017

Advances in Experimental Medicine and Biology

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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.

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Challenges and achievements in the therapeutic modulation of aquaporin functionality

Cited by 48 publications

References 191 publications

Aquaporins in Health and Disease: An Overview Focusing on the Gut of Different Species

Aquaporins in Health and Disease: An Overview Focusing on the Gut of Different Species

The mechanism of aquaporin inhibition by gold compounds elucidated by biophysical and computational methods

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

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