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Framework programme: 6
Call: 4
Project number: LSHP-CT-2006-037760
EC contribution: € 1,103,505
Duration: 36 months
Starting date: January 2007
Graphic element Preparation and Identification of New HIV Reverse Transcriptase
Inhibitors Targeted Against HIV Strains Resistant to anti-HIV/AIDS
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 γ 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 γ. Finally, selected active compounds with low in vitro cytotoxicity will be subjected to in vivo (in mice and/or rats) pharmaco-toxicological investigations.


Human immunodeficiency virus (HIV) encodes for an RNA-dependent DNA polymerase (reverse transcriptase, RT), but not the specific enzymes required for the phosphorylation of 2’,3’-dideoxy- pyrymidine and purine nucleosides. To exert antiviral activity, these analogues must undergo a three-step phosphorylation by host cell kinases and/or be metabolized by other enzymes. Their 5’-triphosphates act as RT competitive inhibitors and/or DNA terminators. Since RT is essential to HIV replication, the development of RT inhibitors is a key strategy in the fight against AIDS. But drug resistance emerges rapidly with these nucleoside-based inhibitors (NRTIs). At present, the emergence of HIV-1 variants resistant to standard drugs is one of the major obstacles to chemotherapy of HIV-1 infection. HIV-1 can develop multidrug resistance in patients receiving various combination chemotherapies. Therefore the development of novel compounds especially modified 2’,3’- dideoxynucleosides, which are active against wild-type as well as multidrug-resistant variants, is urgently needed.


The general aim of this project is to identify and prepare and identify new potential drugs from the class of new modified 2’,3’-dideoxynucleosides, active against HIV-1 drug-resistant laboratory and clinical strains.

Expected results:

To obtain new modified 2’, 3’-dideoxynucleosides and their phosphates; highly active drugs against drug-resistant HIV strains, and to detect their physico-chemical and biological properties. Results will be disseminated through patenting.

Potential applications:

After obtaining positive biological results, patents and publications will be submitted to a pharmaceutical firm (SME) for further investigations in animals and in the clinic, allowing potential outlicensing of the above-mentioned drugs.


Prof. Tadeusz Kulikowski
Instytut Biochemii iBiofizyki PAN
5a Pawinskiego St
02-106 Warszawa
Tel: +48 22 592 3507
Fax: +48 22 6584636


Official Address Other Information
2Kazimierz Kita Instytut Przemyslu Organicznego Oddzia w Pszczynie
27 Doswiadczalna St.
43-200 Pszczyna
Tel: +48 (32) 210 30 81
Fax: +48 (32) 210 35 37
3 Marek Figlerowicz Instytut Chemii Bioorganicznej PAN
12/14 Noskowskiego St.
61-701 Poznan
Tel: +48 61 852 8503
Fax: +48 61 852 0532
E-Mail :
4 Patricia Laquel-Robert UMR 5097 CNRS/Université Bordeaux
2, Rue Léo Saignat 146
33076 Bordeaux
Tel: +(33)5 57 57 17 58
Fax: +(33)5 57 57 17 66
5Andrzej Piasek Instytut Medycyny Doswiadczalnej i
Klinicznej im. M. Mossakowskiego PAS
5 Pawinskiego St.
02-106 warszawa
Tel: +48 (22) 841 4071 ext. 464
Fax: +48 (22) 841 2949
6 Francois Hamy In Pheno AG, Socinstrasse 55a,
CH4051 Basel
Tel: +41 61 267 3542
Fax: +41 61 267 3538

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