The function of many human ARTDs is still unknown. One of our goals is to develop selective inhibitors, which would make it possible to study and verify the biological functions of the enzymes. This strategy would potentially also create new drug leads, as many of the enzymes appear to have functions and interactions that are potentially of pharmaceutical interest.
One of the important goals of the group is to develop effective and robust methods to screen inhibitors and especially to efficiently test the inhibitors against members of the human ARTD family. We also aim to optimize biophysical techniques for measuring compound affinities. Regarding assay development, our next challenge is to establish assays for all human ARTD enzymes.
Structural information that is available and new crystal structures we have solved help us in structure-based drug design and in achieving selectivity of the inhibitors. We aim to use the inhibitors discovered, through screening of compound libraries, to understand the selectivity of the compounds and subsequently use computational methods to find new compounds and improve the selectivity further.
Further development of tankyrase inhibition by selected scaffolds has already resulted in over 40 new crystal structures. The selectivity determinants of these compounds and their efficacy in cellular models will help in tankyrase inhibitor development and hopefully facilitate their progress to drugs.
We aim to understand molecular details of the activation mechanisms of Trypanosoma brucei and cruzi ARTDs and to study the effects of their inhibition in these related human parasites. We also aim to understand the mechanisms of the human ARTD enzymes better through the use of activity assays and structural studies. There are many unanswered questions regarding mechanisms, activation and interactions within this enzyme class. The proteins contain multiple domains and we will use X-ray crystallography and small angle X-ray scattering with full-length and truncated proteins in order to understand the functions of the proteins.
Last updated: 28.10.2016