Objectif
Tuberculosis (TB) is a common and deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis (MTB). In the developed world, the advent of powerful antibiotics and a concerted inoculation program saw the near extinction of TB. However, the rise of drug-resistant strains, HIV infections, and the neglect of TB control programs have increased the urgency for an alternative treatment and diagnosis. Since the presence of L-rhamnose and trehalose [α-D-Glc-(1↔1)-α-D-Glc] motifs in MTB have been associated with disease states, the preparation of modified derivatives constitute excellent research tools to investigate the infective process and offer themselves as potential therapeutic agents. These two sugars are not found in mammalian biology and therefore provide a powerful handle for distinguishing pathogen (MTB) from host (man) both during diagnosis and treatment. In particular, 2-deoxy-2-fluoroglycosides are compounds of increasing importance in biochemistry and medicinal research, especially as antiviral agents, cancer diagnosis probes, and labelling substrates for many biological studies. In addition, 2-deoxy-2-fluoroglycosides have been found particularly useful in the determination of the molecular mechanism of glycosidases and glycosyltransferases by trapping key enzymatic intermediates. We propose a program targeted at the development of innovative methodologies for the preparation of fluorosugars and glycolipid analogues that will allow direct imaging and treatment of TB. The specific goals include: a) Synthesis of 2-deoxy-2-fluoro-rhamnose and trehalose derivatives. b) Synthesis of CD1b-binding glycolipids with variations either at the glycoside and the lipid moieties. c) The use of fluoroglycosides as mechanistic probes, inhibitors, and imaging agents (alternative TB treatment and diagnosis: 18F PET and 19F NMR/MRI).
Champ scientifique
- medical and health scienceshealth sciencesinfectious diseases
- medical and health scienceshealth sciencesinfectious diseasesRNA virusesHIV
- medical and health sciencesclinical medicinepneumologytuberculosis
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
- natural sciencesbiological sciencesmolecular biology
Mots‑clés
Appel à propositions
FP7-PEOPLE-2007-2-1-IEF
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Régime de financement
MC-IEF - Intra-European Fellowships (IEF)Coordinateur
OX1 2JD Oxford
Royaume-Uni