Objectif
The objectives are (i) to obtain profound insights into the molecular resistance mechanisms of HIV against reverse transcriptase inhibitors; (ii) to define the HIV-1-specific NNRTI pocket on RT by crystallography and computer-assisted drug modelling techniques; (iii) to characterize a putative HIV-2-specific lipophylic binding pocket on HIV-2 RT; (iv) to formulate novel concepts and modalities to suppress, delay or control resistance development of HIV-1 against NNRTIs; (v) to investigate new tools to select for attenuated mutant virus strains.
To achieve our goals, a multidisciplinary approach will be followed, including novel drug design and synthesis, modelling of drugs in the HIV-1 RT pocket, X-ray crystallography, virology, molecular biology, cell biology and enzymology. Resistance development of HIV-1 will be performed under a variety of experimental conditions, and the emerging mutant viruses will be geno- and phenotypically characterized, starting from a wild-type, NNRTI- and NRTI-resistance HIV-1 RT background. A search will also be performed for a putative NNRTI-specific binding pocket on HIV-2 RT that may be analogous to the NNRTI-specific HIV-1 RT pocket by the use of NNRTIs that also show activity against HIV-2.
A comparative research will be performed on resistance development of HIV-1 against NNRTIs and NRTIs in lymphocytes and monocyte/macrophages. In this respect the effect of transient changes of cytosolic purine and pyrimidine (deoxy)nucleotide pool ratios during HIV-1 replication on the drug resistance development will be investigated in the presence of NRTIs and NNRTIs. Antimetabolites such as deoxycoformycine, methotrexate, hydroxyurea, hadacidine, mycophenolic acid and others will be included in this study. Co-crystallisation and modelling studies of HIV-1 RT with the thiocarboxanilide NNRTI UC-781, with TSAO-m3T and with their derivatives will be performed to obtain detailed insights in the interaction sites of the drugs with HIV-1 RT and to enable rational design of novel NNRTI derivatives that are more potent in their activity against wild-type and resistant virus strains.
Champ scientifique (EuroSciVoc)
CORDIS classe les projets avec EuroSciVoc, une taxonomie multilingue des domaines scientifiques, grâce à un processus semi-automatique basé sur des techniques TLN.
CORDIS classe les projets avec EuroSciVoc, une taxonomie multilingue des domaines scientifiques, grâce à un processus semi-automatique basé sur des techniques TLN.
- sciences naturellessciences biologiquesmicrobiologievirologie
- sciences médicales et de la santémédecine fondamentalechimie médicinale
- sciences naturellessciences de la Terre et sciences connexes de l'environnementgéologieminéralogiecristallographie
- sciences médicales et de la santésciences de la santémaladie infectieusevirus à ARNVIH
- sciences médicales et de la santémédecine fondamentalepharmacologie et pharmacierésistance aux médicaments
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Appel à propositions
Data not availableRégime de financement
CSC - Cost-sharing contractsCoordinateur
3000 LOUVAIN / LEUVEN
Belgique