Crystallographic study of the mechanisms of inhibition of IDO and TDO enzymes through protein engineering: help in the design of mixed inhibitors as potential anticancer agents.

Project: Research

Description

Cancer is a leading cause of death in the world, especially in developed
countries. To fight against it, a therapeutic arsenal has been developed
including cancer immunotherapy, a recent and promising option.
The indoleamine 2,3-dioxygenase (hIDO) and tryptophan 2,3-dioxygenase
(hTDO) catalyze the dioxygenation of L-tryptophan to form the Nformylkynurenine
and therefore regulate the levels of tryptophan in the
body. Overexpression of these enzymes in many cancers causes a local
depletion of tryptophan which induces tolerance to the host immune system
and allows tumor cells to avoid immune rejection. Therefore, these enzymes
are attractive targets in the context of anti-cancer immunotherapy.
The aim of our project is to identify and develop inhibitors of human
enzymes hIDO and hTDO through a better understanding of the catalytic
and inhibition mechanisms of these systems at the molecular level.
Crystallography is the method of choice to achieve this objective. It will be
combined with enzymatic characterizations and mutagenesis to obtain high
resolution crystallographic structures.
To achieve this ambitious objective, we will use molecular engineering
through the construction of mutants of surface to facilitate the crystallization
of enzymes. These new constructs will then be used to determine the
structures of enzyme-inhibitor complexes with high resolution.
A series of mutations in the active site will also be created for a better
understanding of the mechanism and the substrate specificity of the two
enzymes. This approach will help in the design of mixed inhibitors of hIDO
and hTDO.
StatusFinished
Effective start/end date1/09/1430/09/15