title: Discovery of small molecule vanin inhibitors: new tools to study metabolism and disease.
abstract: 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-α 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.
authors.affiliation: Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Patrick A M
authors.initials: PA
authors.lastname: Jansen
authors.forename: Janna A
authors.initials: JA
authors.lastname: van Diepen
authors.forename: Bas
authors.initials: B
authors.lastname: Ritzen
authors.forename: Patrick L J M
authors.initials: PL
authors.lastname: Zeeuwen
authors.forename: Ivana
authors.initials: I
authors.lastname: Cacciatore
authors.forename: Catia
authors.initials: C
authors.lastname: Cornacchia
authors.forename: Ivonne M J J
authors.initials: IM
authors.lastname: van Vlijmen-Willems
authors.forename: Erik
authors.initials: E
authors.lastname: de Heuvel
authors.forename: Peter N M
authors.initials: PN
authors.lastname: Botman
authors.forename: Richard H
authors.initials: RH
authors.lastname: Blaauw
authors.forename: Pedro H H
authors.initials: PH
authors.lastname: Hermkens
authors.forename: Floris P J T
authors.initials: FP
authors.lastname: Rutjes
authors.forename: Joost
authors.initials: J
authors.lastname: Schalkwijk
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002417:Cattle; D004194:Disease; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010204:Pantetheine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D058851:GPI-Linked Proteins; D054852:Small Molecule Libraries; D010204:Pantetheine; D000581:Amidohydrolases; C022314:pantetheinase