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Preparation and Identification of New HIV Reverse Transcriptase
Inhibitors Targeted Against HIV Strains Resistant to anti-HIV/AIDS drugs
Framework programme:
Project number:
EC contribution:
€ 1,103,505
36 months
Starting date:
January 2007

Keywords: Chronic diseases, virology, anti-HIV and AIDS drugs


HIV-1 can develop multidrug resistance in patients receiving various combination chemotherapies. This is one of main problems in anti-HIV/AIDS chemotherapy. To identify compounds active against HIV-1 drug-resistant strains, project partners plan to synthesise and investigate the structure, conformation and selected physicochemical and biological properties of a range of new and known, modified 2’, 3’-dideoxynucleoside analogues.

Compounds of this type should act as competitive drug-resistant reverse transcriptase (RT-Res) inhibitors. Slow releasing forms of these compounds (prodrugs) will also be prepared. Drug-resistant reverse transcriptases will be obtained from engineered HIV-1 drug-resistant mutants, as well as by recombinant techniques. Interactions of synthesized compounds with the wild type HIV-1 RT, as well as with HIV-1-Res RT, will be investigated and potent inhibitors will be subjected to antiviral activity determinations in cell cultures and in vitro cytotoxicity.

Structure-activity relationships will be performed and selected RT inhibitors will be subjected to determination of complete cross-resistant profiles in laboratory and clinical HIV-1 strains from documented clinical context of resistance. Investigation of in vitro viral escape will also be determined. Long-term antiretroviral therapy often results in toxic adverse events attributable to mitochondrial damage due to the inhibition of DNA polymerase ? synthesis and the reduction of cellular energy production.

The toxicity of the new drugs will be evaluated by determining the inhibitory properties (IC50) and insertion and exonucleolytic removal of new nucleoside analogues by DNA polymerase ?. Finally, selected active compounds with low in vitro cytotoxicity will be subjected to in vivo (in mice and/or rats) pharmaco-toxicological investigations.

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