Journal of Biotechnology & Biomaterials
Open Access

Abstract

Human indoleamine 2,3-dioxygenase 1 (IDO) catalyzes the conversion of L-tryptophan (L-Trp) to N-formylkynurenine through a heme and O2-dependent oxidation process. IDO is recognized as a central regulator of immune responses in a broad variety of physiological and pathological settings and is thus considered an attractive therapeutic target. In search of novel IDO inhibitors, we identified 4-amino-1,2,3-triazoles. Using crystallographic, biochemical and spectroscopic techniques we have fully characterized a representative molecule of this molecular series (VIDOi1) and shown that: VIDOi1 is non-competitive for D-Trp; VIDOi1 interacts with the IDO heme iron VIDOi1 binds to both the ferric and the ferrous form of the enzyme; VIDOi1establishes a slow complex with the ferrous form of IDO; and the VIDOi1-IDO complex is long-lived. The generation of this tight binding complex between IDO and the 4-amino -1,2,3-triazoles leads to exceptional potencies of this molecule series in a cellular context.

Biography

Julie Alexandre is specialized in Kinetics at the Vertex Pharmaceuticals Europe Ltd., (Abingdon, UK). She holds a PhD in Biochemistry from the University of Edinburgh (Scotland, UK) and undertook Post-doctoral Research in Enzymology at the Pierre-and-Marie-Curie University (Paris, France). She has been working at Vertex since 9 years and has contributed in many internal drug discovery efforts in oncology, targeting kinases, proteases and redox enzymes, through characterization of enzymes substrates and inhibitors kinetics and mode of action.

Email: julie_alexandre@vrtx.com