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Identification and characterization of potent and selective aquaporin-3 and aquaporin-7 inhibitors

Sonntag, Yonathan LU ; Gena, Patrizia ; Maggio, Anna ; Singh, Tania LU ; Artner, Isabella LU ; Oklinski, Michal K ; Johanson, Urban LU orcid ; Kjellbom, Per LU ; Nieland, John Dirk and Nielsen, Søren , et al. (2019) In Journal of Biological Chemistry 294(18). p.7377-7387
Abstract

The aquaglyceroporins are a subfamily of aquaporins that conduct both water and glycerol. Aquaporin-3 (AQP3) has an important physiological function in renal water reabsorption, and AQP3-mediated hydrogen peroxide (H2O2) permeability can enhance cytokine signaling in several cell types. The related aquaglyceroporin AQP7 is required for dendritic cell chemokine responses and antigen uptake. Selective small-molecule inhibitors are desirable tools for investigating the biological and pathological roles of these and other AQP isoforms. Here, using a calcein fluorescence quenching assay we screened a library of 7360 drug-like small molecules for inhibition of mouse AQP3 water permeability. Hit confirmation and expansion with commercially... (More)

The aquaglyceroporins are a subfamily of aquaporins that conduct both water and glycerol. Aquaporin-3 (AQP3) has an important physiological function in renal water reabsorption, and AQP3-mediated hydrogen peroxide (H2O2) permeability can enhance cytokine signaling in several cell types. The related aquaglyceroporin AQP7 is required for dendritic cell chemokine responses and antigen uptake. Selective small-molecule inhibitors are desirable tools for investigating the biological and pathological roles of these and other AQP isoforms. Here, using a calcein fluorescence quenching assay we screened a library of 7360 drug-like small molecules for inhibition of mouse AQP3 water permeability. Hit confirmation and expansion with commercially available substances identified the ortho-chloride-containing compound DFP00173, which inhibited mouse and human AQP3 with an IC50 of ~0.1-0.4 μM but had low efficacy toward mouse AQPs 7 and 9. Surprisingly, inhibitor specificity testing revealed that the methylurea-linked compound Z433927330, a partial AQP3 inhibitor (IC50 ~0.7-0.9 μM), is a potent and efficacious inhibitor of mouse AQP7 water permeability (IC50 ~0.2 μM). Stopped-flow light-scattering measurements confirmed that DFP00173 and Z433927330 inhibit AQP3 glycerol permeability in human erythrocytes. Moreover, DFP00173, Z433927330, and the previously identified AQP9 inhibitor RF03176 blocked aquaglyceroporin H2O2 permeability. Molecular docking to AQP3, AQP7, and AQP9 homology models suggested interactions between these inhibitors and aquaglyceroporins at similar binding sites. DFP00173 and Z433927330 constitute selective and potent AQP3 and AQP7 inhibitors, respectively, and contribute to a set of isoform-specific aquaglyceroporin inhibitors that will facilitate the evaluation of these AQP isoforms as drug targets.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
294
issue
18
pages
20 pages
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • pmid:30862673
  • scopus:85065638439
ISSN
1083-351X
DOI
10.1074/jbc.RA118.006083
language
English
LU publication?
yes
additional info
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
id
e0ed00b8-de45-47c0-a9f0-923487db263e
date added to LUP
2019-03-18 08:21:35
date last changed
2024-04-01 23:43:16
@article{e0ed00b8-de45-47c0-a9f0-923487db263e,
  abstract     = {{<p>The aquaglyceroporins are a subfamily of aquaporins that conduct both water and glycerol. Aquaporin-3 (AQP3) has an important physiological function in renal water reabsorption, and AQP3-mediated hydrogen peroxide (H2O2) permeability can enhance cytokine signaling in several cell types. The related aquaglyceroporin AQP7 is required for dendritic cell chemokine responses and antigen uptake. Selective small-molecule inhibitors are desirable tools for investigating the biological and pathological roles of these and other AQP isoforms. Here, using a calcein fluorescence quenching assay we screened a library of 7360 drug-like small molecules for inhibition of mouse AQP3 water permeability. Hit confirmation and expansion with commercially available substances identified the ortho-chloride-containing compound DFP00173, which inhibited mouse and human AQP3 with an IC50 of ~0.1-0.4 μM but had low efficacy toward mouse AQPs 7 and 9. Surprisingly, inhibitor specificity testing revealed that the methylurea-linked compound Z433927330, a partial AQP3 inhibitor (IC50 ~0.7-0.9 μM), is a potent and efficacious inhibitor of mouse AQP7 water permeability (IC50 ~0.2 μM). Stopped-flow light-scattering measurements confirmed that DFP00173 and Z433927330 inhibit AQP3 glycerol permeability in human erythrocytes. Moreover, DFP00173, Z433927330, and the previously identified AQP9 inhibitor RF03176 blocked aquaglyceroporin H2O2 permeability. Molecular docking to AQP3, AQP7, and AQP9 homology models suggested interactions between these inhibitors and aquaglyceroporins at similar binding sites. DFP00173 and Z433927330 constitute selective and potent AQP3 and AQP7 inhibitors, respectively, and contribute to a set of isoform-specific aquaglyceroporin inhibitors that will facilitate the evaluation of these AQP isoforms as drug targets.</p>}},
  author       = {{Sonntag, Yonathan and Gena, Patrizia and Maggio, Anna and Singh, Tania and Artner, Isabella and Oklinski, Michal K and Johanson, Urban and Kjellbom, Per and Nieland, John Dirk and Nielsen, Søren and Calamita, Giuseppe and Rützler, Michael}},
  issn         = {{1083-351X}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{18}},
  pages        = {{7377--7387}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Biological Chemistry}},
  title        = {{Identification and characterization of potent and selective aquaporin-3 and aquaporin-7 inhibitors}},
  url          = {{http://dx.doi.org/10.1074/jbc.RA118.006083}},
  doi          = {{10.1074/jbc.RA118.006083}},
  volume       = {{294}},
  year         = {{2019}},
}