Chemical, biochemical and molecular approaches to the study of the mechanism of action of HIV integrase and reverse transcriptase and search of specific inhibitors

Project Information

Grant agreement ID: INTAS-RFBR95-1214

Start date

End date

Funded under

• International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993-

Total cost No data

EU contribution No data

Coordinated by

Centre National de la Recherche Scientifique
France

Objective

The research topic deals with the structure-function relationship of the RT of the HIV of type 1 and 2, several mutant forms of HIV-1 RT and integrase. R T is crucial in the replication cycle of the retrovirus: the role of RT is to synthesize the double stranded proviral DNA from the retroviral RNA genome. The proviral DNA is then integrated into the host nuclear genome in a reaction catalyzed by viral integrase (IN). Both enzymes are the main targets of the therapeutical treatment of AIDS.

Recently we have developed new kinetic and thermodynamic approaches for analysis of protein-nucleic acids recognition, which make it possible to reveal the individual nucleotide unit contribution to the single and double-stranded nucleic acids interactions with the recognizing enzymes. Structural analysis of HIV-1 RT was done by methods of crosslinking and highly selective affinity modification and other different physico-chemical approaches. A detailed analysis of the mechanism of various natural substrate recognition by RT and its mutant form as well as by integrase using various methods will be done. Better understanding of the biochemical mechanism of action of the enzymes and of the difference in functioning of RT mutant forms may help us to design new drugs with higher inhibitory activity as well as with decreased potential for resistance. Inhibitor capacity of nucleotide and oligonucleotide containing several new organic compounds as well as new non-natural oligopepetides interacting with small grove of DNA and stabilizing interaction of specific sequence strands will be used.

According to our previous data HIV integrase most probably possess the additional enzymatic activities: it is capable to convert ATP to unusual products like ppAppA, ppA pppA an so on, and to self-phosphorylate in the presence of ATP. The detailed analysis of the mechanism of integrase functioning in order to establish the proposed functions is planed.

Programme(s)

• IC-INTAS - International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993-

Topic(s)

• 4 - Life Sciences

Call for proposal

Data not available

Funding Scheme

Data not available

Coordinator

Centre National de la Recherche Scientifique

• EU contribution: No data
• Address: 33077 Bordeaux ; France
• Total cost: No data

Participants (1)

Novosibirsk Institute of Bioorganic Chemistry

Russia

• EU contribution: No data
• Address: 630090 Novosibirsk
• Total cost: No data