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J Biol Chem. 2015 Jul 3;290(27):16861-72. doi: 10.1074/jbc.M114.629964. Epub 2015 May 22.

Structure Guided Chemical Modifications of Propylthiouracil Reveal Novel Small Molecule Inhibitors of Cytochrome b5 Reductase 3 That Increase Nitric Oxide Bioavailability.

Author information

1
From the Heart, Lung, Blood, and Vascular Medicine Institute.
2
Department of Computational and Systems Biology.
3
From the Heart, Lung, Blood, and Vascular Medicine Institute, Department of Pharmacology and Chemical Biology, and.
4
From the Heart, Lung, Blood, and Vascular Medicine Institute, Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
5
Department of Pharmacology and Chemical Biology, and.
6
Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
7
From the Heart, Lung, Blood, and Vascular Medicine Institute, Department of Pharmacology and Chemical Biology, and astraub@pitt.edu.

Abstract

NADH cytochrome b5 reductase 3 (CYB5R3) is critical for reductive reactions such as fatty acid elongation, cholesterol biosynthesis, drug metabolism, and methemoglobin reduction. Although the physiological and metabolic importance of CYB5R3 has been established in hepatocytes and erythrocytes, emerging investigations suggest that CYB5R3 is critical for nitric oxide signaling and vascular function. However, advancement toward fully understanding CYB5R3 function has been limited due to a lack of potent small molecule inhibitors. Because of this restriction, we modeled the binding mode of propylthiouracil, a weak inhibitor of CYB5R3 (IC50 = ∼275 μM), and used it as a guide to predict thiouracil-biased inhibitors from the set of commercially available compounds in the ZINC database. Using this approach, we validated two new potent derivatives of propylthiouracil, ZINC05626394 (IC50 = 10.81 μM) and ZINC39395747 (IC50 = 9.14 μM), both of which inhibit CYB5R3 activity in cultured cells. Moreover, we found that ZINC39395747 significantly increased NO bioavailability in renal vascular cells, augmented renal blood flow, and decreased systemic blood pressure in response to vasoconstrictors in spontaneously hypertensive rats. These compounds will serve as a new tool to examine the biological functions of CYB5R3 in physiology and disease and also as a platform for new drug development.

KEYWORDS:

computational biology; cytochrome b5 reductase 3; hemoglobin; nitric oxide; oxidation-reduction (redox); vascular

PMID:
26001785
PMCID:
PMC4505432
DOI:
10.1074/jbc.M114.629964
[Indexed for MEDLINE]
Free PMC Article

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