Probing the Structure, Mechanism and Inhibition of Indoleamine 2,3-Dioxygenase Using Structure- and Ligand-Based Studies [ 2004 - 2006 ]

Research Grant

Researchers: A/Pr Joanne Jamie (Principal investigator) ,  Dr Galina Polekhina ,  Prof Roger Truscott

Brief description The human enzyme indoleamine 2,3-dioxygenase (IDO) is responsible for the initiation of a major enzymatic pathway, known as the kynurenine pathway. During certain immune and infectious diseases IDO becomes over-active and this leads to accumulation of neurotoxic kynurenine pathway compounds (metabolites). The elevated levels of these metabolites have been linked to severe mental deterioration associated with diseases such as AIDS (AIDS dementia complex), malaria and Alzheimer's disease. Several kynurenine pathway metabolites have also been linked to age-related nuclear cataract, which is the major cause of human blindness. This project employs a multidisciplinary approach that brings together a team of expert scientists from medicinal chemistry, protein crystallography, protein biochemistry and neurology. The overall aims of the project are to determine the structure of IDO using the recombinant human enzyme that we have cloned and expressed in an active form and to develop compounds that will regulate levels of the kynurenine pathway metabolites by selectively inhibiting the action of IDO. In addition, we will begin to assess the medicinal value of the best inhibitors. We have already synthesised several inhibitors of IDO, but wish to design more potent inhibitors. In order to do this, computer-aided molecular modelling and X-ray crystallography (which effectively provides a picture of the enzyme with the inhibitors attached) will be used to predict the best molecular features needed for inhibition. This will greatly aid the design of new inhibitor compounds, which will then be synthesised. The best inhibitors will also be examined to determine their general pharmacological value and specifically their ability to treat AIDS dementia complex and age-related nuclear cataract. These enzyme inhibitors also have the potential to treat other significant human diseases.

Funding Amount $AUD 319,650.00

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant