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Biochem J. 2018 Sep 25;475(18):2941-2953. doi: 10.1042/BCJ20180065.

Chemical validation and optimization of pharmacoperones targeting vasopressin type 2 receptor mutant.

Author information

1
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A. jody.janovick@ttuhsc.edu.
2
Lead Identification Division, Translational Research Institute and Department of Molecular Medicine, Scripps Research Institute, Jupiter, FL 33458, U.S.A.
3
Department of Chemistry, Scripps Research Institute, Jupiter, FL 33458, U.S.A.
4
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A.

Abstract

A series of compounds formerly identified by high-throughput screening was studied for their ability to serve as pharmacoperones for the vasopressin type 2 receptor (V2R) mutant L83Q, which is known to cause nephrogenic diabetes insipidus (NDI). Three compounds were particularly effective in rerouting the mutant receptor in a concentration-dependent manner, were neither agonists nor antagonists, and displayed low cellular toxicity. Compound 1 was most effective and can be used as a molecular probe for future studies of how small molecules may affect NDI caused by mutant V2R. These compounds, however, failed to rescue the V2R Y128S mutant, indicating that the compounds described may not work in the rescue of all known mutants of V2R. Taken collectively, the present studies have now identified a promising lead compound that could function as a pharmacoperone to correct the trafficking defect of the NDI-associated mutant V2R L83Q and thus has the therapeutic potential for the treatment of NDI.

KEYWORDS:

nephrogenic diabetes insipidus; pharmacoperone; trafficking mutants; vasopressin receptor

PMID:
30068530
DOI:
10.1042/BCJ20180065
[Indexed for MEDLINE]

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