Inhibitors of Mammalian Aquaporin Water Channels

Mohammed Abir-Awan, Philip Kitchen, Mootaz M. Salman, Matthew T. Conner, Alex C. Conner, Roslyn M. Bill

Research output: Contribution to journalReview article

Abstract

Aquaporins (AQPs) are water channel proteins that are essential to life, being expressed in all kingdoms. In humans, there are 13 AQPs, at least one of which is found in every organ system. The structural biology of the AQP family is well-established and many functions for AQPs have been reported in health and disease. AQP expression is linked to numerous pathologies including tumor metastasis, fluid dysregulation, and traumatic injury. The targeted modulation of AQPs therefore presents an opportunity to develop novel treatments for diverse conditions. Various techniques such as video microscopy, light scattering and fluorescence quenching have been used to test putative AQP inhibitors in both AQP-expressing mammalian cells and heterologous expression systems. The inherent variability within these methods has caused discrepancy and many molecules that are inhibitory in one experimental system (such as tetraethylammonium, acetazolamide, and anti-epileptic drugs) have no activity in others. Some heavy metal ions (that would not be suitable for therapeutic use) and the compound, TGN-020, have been shown to inhibit some AQPs. Clinical trials for neuromyelitis optica treatments using anti-AQP4 IgG are in progress. However, these antibodies have no effect on water transport. More research to standardize high-throughput assays is required to identify AQP modulators for which there is an urgent and unmet clinical need.

Original languageEnglish
Article number1589
JournalInternational Journal of Molecular Sciences
Volume20
Issue number7
DOIs
Publication statusPublished - 29 Mar 2019

Fingerprint

Aquaporins
inhibitors
acetazolamide
pathology
metastasis
Pathology
heavy metals
antibodies
Heavy ions
biology
Antibodies
organs
Light scattering
water
Modulators
Heavy metals
health
Metal ions
Tumors
Water

Bibliographical note

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Keywords

  • AQP expression
  • AQP inhibitors
  • AQP modulators
  • AQP structure
  • AQPs in disease
  • Aquaporin
  • Functional assays
  • Heavy metals
  • Small molecule inhibitors
  • TGN-020

Cite this

Abir-Awan, Mohammed ; Kitchen, Philip ; Salman, Mootaz M. ; Conner, Matthew T. ; Conner, Alex C. ; Bill, Roslyn M. / Inhibitors of Mammalian Aquaporin Water Channels. In: International Journal of Molecular Sciences. 2019 ; Vol. 20, No. 7.
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Inhibitors of Mammalian Aquaporin Water Channels. / Abir-Awan, Mohammed; Kitchen, Philip; Salman, Mootaz M.; Conner, Matthew T.; Conner, Alex C.; Bill, Roslyn M.

In: International Journal of Molecular Sciences, Vol. 20, No. 7, 1589, 29.03.2019.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Inhibitors of Mammalian Aquaporin Water Channels

AU - Abir-Awan, Mohammed

AU - Kitchen, Philip

AU - Salman, Mootaz M.

AU - Conner, Matthew T.

AU - Conner, Alex C.

AU - Bill, Roslyn M.

N1 - © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

PY - 2019/3/29

Y1 - 2019/3/29

N2 - Aquaporins (AQPs) are water channel proteins that are essential to life, being expressed in all kingdoms. In humans, there are 13 AQPs, at least one of which is found in every organ system. The structural biology of the AQP family is well-established and many functions for AQPs have been reported in health and disease. AQP expression is linked to numerous pathologies including tumor metastasis, fluid dysregulation, and traumatic injury. The targeted modulation of AQPs therefore presents an opportunity to develop novel treatments for diverse conditions. Various techniques such as video microscopy, light scattering and fluorescence quenching have been used to test putative AQP inhibitors in both AQP-expressing mammalian cells and heterologous expression systems. The inherent variability within these methods has caused discrepancy and many molecules that are inhibitory in one experimental system (such as tetraethylammonium, acetazolamide, and anti-epileptic drugs) have no activity in others. Some heavy metal ions (that would not be suitable for therapeutic use) and the compound, TGN-020, have been shown to inhibit some AQPs. Clinical trials for neuromyelitis optica treatments using anti-AQP4 IgG are in progress. However, these antibodies have no effect on water transport. More research to standardize high-throughput assays is required to identify AQP modulators for which there is an urgent and unmet clinical need.

AB - Aquaporins (AQPs) are water channel proteins that are essential to life, being expressed in all kingdoms. In humans, there are 13 AQPs, at least one of which is found in every organ system. The structural biology of the AQP family is well-established and many functions for AQPs have been reported in health and disease. AQP expression is linked to numerous pathologies including tumor metastasis, fluid dysregulation, and traumatic injury. The targeted modulation of AQPs therefore presents an opportunity to develop novel treatments for diverse conditions. Various techniques such as video microscopy, light scattering and fluorescence quenching have been used to test putative AQP inhibitors in both AQP-expressing mammalian cells and heterologous expression systems. The inherent variability within these methods has caused discrepancy and many molecules that are inhibitory in one experimental system (such as tetraethylammonium, acetazolamide, and anti-epileptic drugs) have no activity in others. Some heavy metal ions (that would not be suitable for therapeutic use) and the compound, TGN-020, have been shown to inhibit some AQPs. Clinical trials for neuromyelitis optica treatments using anti-AQP4 IgG are in progress. However, these antibodies have no effect on water transport. More research to standardize high-throughput assays is required to identify AQP modulators for which there is an urgent and unmet clinical need.

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KW - AQP inhibitors

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KW - AQP structure

KW - AQPs in disease

KW - Aquaporin

KW - Functional assays

KW - Heavy metals

KW - Small molecule inhibitors

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UR - https://www.mdpi.com/1422-0067/20/7/1589

U2 - 10.3390/ijms20071589

DO - 10.3390/ijms20071589

M3 - Review article

C2 - 30934923

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

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