title: Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders.
abstract: Abnormal levels of kynurenic acid (KYNA) in the human brain are believed to be connected to several central nervous system (CNS) diseases, therefore compounds which affect the production of this crucial metabolite are of interest in CNS drug development. The majority of KYNA production is accounted for by kynurenine aminotransferase-2 (KAT-2) in the mammalian brain; hence this enzyme is one of the most interesting targets with which to modulate KYNA levels. Recently developed human KAT-2 inhibitors with high potencies are known to irreversibly bind to the enzyme cofactor, pyridoxal-5'-phosphate (PLP), which may lead to severe side effects due to the abundance of PLP-dependent enzymes. In this study, we report a reversible and competitive inhibitor of KAT-2. Its inhibitory activities were examined using HPLC and surface plasmon resonance (SPR) and compare favorably with other recently reported KAT-2 inhibitors. Our inhibitor, NS-1502, demonstrates suitable inhibitory activity, almost 10 times more potent than the known reversible KAT-2, (S)-ESBA.
authors.affiliation: Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. anem7250@uni.sydney.edu.au.
authors.forename: Alireza
authors.initials: A
authors.lastname: Nematollahi
authors.affiliation: Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. gsun2866@uni.sydney.edu.au.
authors.forename: Guanchen
authors.initials: G
authors.lastname: Sun
authors.affiliation: Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. gjay8197@uni.sydney.edu.au.
authors.forename: Gayan S
authors.initials: GS
authors.lastname: Jayawickrama
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. jane.hanrahan@sydney.edu.au.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Hanrahan
authors.affiliation: Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. bret.church@sydney.edu.au.
authors.forename: W Bret
authors.initials: WB
authors.lastname: Church
mesh_terms: D002384:Catalysis; D003072:Cognition Disorders / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D011485:Protein Binding; D013329:Structure-Activity Relationship; D000637:Transaminases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase
keywords: (S)-ESBA; BFF-122; Kynurenine aminotransferase-2; PF-04859989; SPR