Discovery of Small Molecule Vanin Inhibitors: New Tools To Study Metabolism and Disease

被引：43

作者：

Jansen, Patrick A. M. ^{[1
]}

van Diepen, Janna A. ^{[2
]}

Ritzen, Bas ^{[3
]}

Zeeuwen, Patrick L. J. M. ^{[1
]}

Cacciatore, Ivana ^{[4
]}

Cornacchia, Catia ^{[4
]}

van Vlijmen-Willems, Ivonne M. J. J. ^{[1
]}

de Heuvel, Erik ^{[5
]}

Botman, Peter N. M. ^{[5
]}

Blaauw, Richard H. ^{[5
]}

Hermkens, Pedro H. H. ^{[3
]}

Rutjes, Floris P. J. T. ^{[3
]}

Schalkwijk, Joost ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Dept Gen Internal Med, Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Inst Mol & Mat, Dept Synthet Organ Chem, Nijmegen, Netherlands

[4] Univ G DAnnunzio, Dept Pharm, Chieti, Italy

[5] Chiralix BV, Nijmegen, Netherlands

来源：

ACS CHEMICAL BIOLOGY | 2013年 / 8卷 / 03期

关键词：

NEUTROPHIL ADHERENCE; HUMAN-LEUKOCYTES; PANTETHEINASE; EXPRESSION; PROTEIN; TISSUE; MOUSE; MICE; CHOLESTEROL; PANTETHINE;

D O I：

10.1021/cb3006424

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Vanins are enzymes with pantetheinase activity and are presumed to play a role in the recycling of pantothenic acid (vitamin B5) from pantetheine. Pantothenic acid is an essential nutrient required to synthesize coenzyme A, a cofactor involved in many biological processes such as fatty acid synthesis and oxidation of pyruvate to fuel the citric acid cycle. Hydrolysis of pantetheine also liberates cysteamine, a known antioxidant. Vanin-1 is highly expressed in liver and is under transcriptional control of PPAR-a and nutritional status, suggesting a role in energy metabolism. The lack of potent and specific inhibitors of vanins has hampered detailed investigation of their function. We hereby report the design, synthesis, and characterization of a novel pantetheine analogue, RR6, that acts as a selective, reversible, and competitive vanin inhibitor at nanomolar concentration. Oral administration of RR6 in rats completely inhibited plasma vanin activity and caused alterations of plasma lipid concentrations upon fasting, thereby illustrating its potential use in chemical biology research.

引用

页码：530 / 534

页数：5

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