Rational Approaches to Pathogen Inhibitor Discovery (RAPID)
Tuberculosis
- Status
- New Project
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- Background
- Tuberculosis (TB) is caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb). Today, one-third of the world’s population is infected with the TB bacillus. About eight millions become infected with TB every year and nearly two million people die. Despite this, no new anti-TB drug has been developed in the last 40 years. There is an urgent need to discover and develop novel therapeutic agents against Mtb. In a multi-disciplinary effort together with structural biology and computational chemistry groups at Uppsala University we are pursuing two different antitubercular drug targets Glutamine Synthetase and Ribonucleotide Reductase. Glutamine Synthetase plays an important role in the bacterium’s cell wall biosynthesis and nitrogen metabolism and it has a potential as an antibacterial target. Ribonucleotide Reductase catalyzes the reduction of ribonucleotides to the corresponding deoxyribonucleotides and is an essential enzyme for DNA synthesis. The active enzyme is a tetramer composed of two large subunits (R1) and two small subunits (R2). The association of the subunits is crucial for enzymatic activity. Ribonucleotide Reductase is a well-known target for cancer therapy and antiviral agents.
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- Aim
- To design and synthesize inhibitors of Glutamine Synthetase and Ribonucleotide Reductase.
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- Method
- In the Glutamine Synthetase project X-ray structures produced by the structural biology group serves as the starting point for virtual screening and structure based drug design efforts. Identified hits will be developed into drug like lead compounds. In the Ribonucleotide Reductase project we utilize the peptide to peptidomimetic approach to derive less peptide-like inhibitors. The starting point in this project is a heptapeptide corresponding to the C-terminal end of the R2 subunit.
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Last modified at 2008-08-12 10:54 by Sorin Srbu
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