Objective
The project is a detailed study of structural and kinetic behaviour of an important class of metabolic enzymes, the nucleotide kineses, which control the phosphorylation state of nucleosides and nucleotides within both normal and virally infected cells. Kinases are key enzymes for the therapeutic intervention as there is a large variation in substrate specificity, between host enzymes and those of bacteria and viruses. A range of powerful biophysical and computational chemistry techniques will be used to study a variety of kineses. In order to acquire high resolution data at as close to atomic level as is possible using current technology, X-ray crystallography techniques will be used in both the static and dynamic mode. Static pictures of the phosphorylation states of the enzymes TMP kineses and HSV-1 TK will be obtained using conventional crystallography and dynamic "snapshots" along the catalytic pathway will be attempted using Laue diffraction techniques. Cycles of X-ray crystallographic structure determination of bound drugs; molecular drug design; synthesis of new drugs will be used to obtain enhanced new pharmaceuticals.
The kineses we shall be initially studying and for which we have X-ray diffraction quality crystals are the TMP kinase from E. Coli and the thymidine kinase from Herpes Simplex type I [TK HSV-1]; subsequent structural studies will be undertaken for the TMP kinase for B. subtilis, M. tuberculosis, H. influenzae, Y. pestis, the thymidine kinase of HSV-2, HMV-8 (Kaposi's sarcoma associated herpes virus) and the human thymidine kinase. The TMP kinase is a very important cancer therapeutic target as it is expressed at different times in the cell cycle. Arising from the major clinical danger of widespread bacterial resistance to the conventional antibiotics developed since 1944, there is a need to identify novel targets within bacteria and selectively inhibit them.
The thymidine kinase from Herpes Simplex virus (HSV) is the major target for current herpes treatment and the widely sold drug aciclovir is primarily used in the clinical management of HSV-1, HSV2 and shingles. Humans are the host for 8 herpes viruses causing a wide range of debilitating and fatal infections. HMV-8 (Karposi's sarcoma associated herpes virus) is widely found in AIDS patients, 25% of whom go on to suffer Kaposi's sarcoma. The expression of the HSV-l TK gene has found wide application in gene therapy especially brain tumour treatment.
Four major goals underpin the project.
(1) X-ray crystallographic structure solution of kineses in complex with their natural substrates
(2) X-ray crystallography of kineses with known inhibitors.
(3) Design of new inhibitors on the basis of the solved structures and for related kineses from other organisms by using homology modelling. (4) Kinetic studies on tertiary complexes with 'caged' natural substrates and drugs using Laue diffraction and/or cryotrapping techniques.
The project will bring together a multi-disciplinary group with a diverse range of expertise from both the academic and the industrial sphere across the KU, in the areas of X-ray crystallography (Dr. Marc Delarue, The Pasteur Institute, Paris, FR; Dr. Mark Sanderson, The Randall Institute, King's College London, GB); Kinetic-Laue X-ray diffraction (Dr. Dominique Bourgeois, ESRF, Grenoble, FR) computational chemistry, molecular modelling (Prof. Modesto Orozco, Dept. of Chemistry, Univ. Barcelona, ES and Dr. David Manallack, Chiroscience, Cambridge, GB) and Organic Chemistry (Dr. Pieter Herdewijn, Rega Institute, University of Leuven, BE).
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences medical biotechnology genetic engineering gene therapy
- medical and health sciences basic medicine medicinal chemistry
- medical and health sciences health sciences infectious diseases RNA viruses influenza
- medical and health sciences health sciences infectious diseases RNA viruses HIV
- medical and health sciences health sciences infectious diseases DNA viruses
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Coordinator
75724 Paris
France
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