Gabriele Costantino1. 1. Università degli Studi di Parma, Dipartimento Farmaceutico, Via GP Usberti 27/A-Campus Universitario, 43100 Parma, Italy. gabriele.costantino@unipr.it
Abstract
BACKGROUND: The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, consists of a cascade of enzymatic reactions eventually leading to NAD(+) formation. Many metabolites along the route have biological activities, especially in the nervous and immune systems. OBJECTIVE/ METHODS: This review focuses on three therapeutic areas, tumor immunoediting, schizophrenia, and Huntington's disease, apparently disconnected but linked by preliminary proof-of-concept of KP involvement. The potential embedded in drug discovery programs aimed at the identification of selective inhibitors with optimized pharmacodynamic and pharmacokinetic properties for human studies is discussed. RESULTS/ CONCLUSIONS: Recent advances have shifted the attention on the kynurenine pathway from a scientific curiosity to a clinically relevant collection of targets. A relatively large number of ligands able to interfere with individual enzymes of the pathway have been made available, but none have so far proceeded into advanced clinical studies.
BACKGROUND: The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, consists of a cascade of enzymatic reactions eventually leading to NAD(+) formation. Many metabolites along the route have biological activities, especially in the nervous and immune systems. OBJECTIVE/ METHODS: This review focuses on three therapeutic areas, tumor immunoediting, schizophrenia, and Huntington's disease, apparently disconnected but linked by preliminary proof-of-concept of KP involvement. The potential embedded in drug discovery programs aimed at the identification of selective inhibitors with optimized pharmacodynamic and pharmacokinetic properties for human studies is discussed. RESULTS/ CONCLUSIONS: Recent advances have shifted the attention on the kynurenine pathway from a scientific curiosity to a clinically relevant collection of targets. A relatively large number of ligands able to interfere with individual enzymes of the pathway have been made available, but none have so far proceeded into advanced clinical studies.
Authors: S B Adams; L A Setton; E Kensicki; M P Bolognesi; A P Toth; D L Nettles Journal: Osteoarthritis Cartilage Date: 2011-10-24 Impact factor: 6.576
Authors: Cynthia O Akagbosu; Gretchen C Evans; Danielle Gulick; Raymond F Suckow; David J Bucci Journal: Schizophr Bull Date: 2010-12-20 Impact factor: 9.306
Authors: Jessica R Adams Wilson; Alessandro Morandi; Timothy D Girard; Jennifer L Thompson; Chad S Boomershine; Ayumi K Shintani; E Wesley Ely; Pratik P Pandharipande Journal: Crit Care Med Date: 2012-03 Impact factor: 7.598
Authors: Francesca M Notarangelo; Hui-Qiu Wu; Anthony Macherone; David R Graham; Robert Schwarcz Journal: Anal Biochem Date: 2011-12-28 Impact factor: 3.365
Authors: Robert D Oades; Aye-Mu Myint; Maria R Dauvermann; Benno G Schimmelmann; Markus J Schwarz Journal: Behav Brain Funct Date: 2010-06-09 Impact factor: 3.759
Authors: Flaviano Giorgini; Shao-Yi Huang; Korrapati V Sathyasaikumar; Francesca M Notarangelo; Marian A R Thomas; Margarita Tararina; Hui-Qiu Wu; Robert Schwarcz; Paul J Muchowski Journal: J Biol Chem Date: 2013-11-04 Impact factor: 5.157
Authors: Olga A Snytnikova; Lyudmila V Kopylova; Elena I Chernyak; Sergey V Morozov; Nataliya G Kolosova; Yuri P Tsentalovich Journal: Mol Vis Date: 2009-12-16 Impact factor: 2.367