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Molecular mechanisms of interactions of DNA-topoisomerases and integrase inhibitors with DNA, enzymes and in ternary complexes

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Several among the most active anticancer drugs poison cellular DNA-topoisomerases (Topo) I and II. The mode of DNA binding is one of the most important but not the only factor in the formation of Topo-mediated ternary cleavable complexes. Therefore the molecular background of interactions within the supra-molecular complexes of enzymes, DNA and anti-tumour drugs should be investigated if the overall patterns of drug structure-activity relationships is to be clarified. The physical basis for cleavable complex formation by Topo-targeting drugs remains to be defined. This project is one of the first to study molecular interactions accompanying this effect, and to analyse the molecular basis of complex formation for the drugs purified with Topo I and II, with the DNA and within the ternary cleavable and reversed complexes by means of Raman, resonance Raman, and SERS techniques.

The main goal of the project is to elucidate the molecular interactions between drugs (specific Topo I, Topo II or dual Topo I and II inhibitors) and their targets, their selectivity for cancer cells and the mechanisms of drug sensitivity, resistance using the normal and drug-resistant cell lines. The microspectroscopic techniques available to the members of the consortium will make it possible to correlate structure-function relationships found in vitro with the intracellular interactions. Therefore it should be possible to design more selective Topo I and II inhibitors, and to shed light on the general mechanisms of action of Topo-targeting anti-tumour drugs.

The second goal of the project is devoted to the study of molecular background and structure-function relationships in the mechanism of interactions responsible for inhibition of human immunodeficiency virus (HIV) integrase by a variety of chemicals, including Topo inhibitors, antimalarial agents, and DNA binders. Each step of the HIV replication cycle represents a potential target for therapeutic intervention. The set-up of an in vitro retroviral DNA integration system using recombinant HIV integrase and oligonucleotides corresponding to the U5 end of HIV DNA will be used to identify several groups of drugs which are able to inhibit effectively HIV-1 integrase (e.g. caffeic acid phenethyl ester, flavon, chloroquine, and anthracyclines). The identified drugs will be studied by means of spectroscopic and microspectroscopic techniques within the scope of the project and their molecular interactions with the target will be analysed both in vitro and in living cells.

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Université de Reims - Champagne -Ardenne
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Rue Cognacq Jay 51
51096 Reims
Frankreich

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Letzte Aktualisierung: 19 September 1996

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Permalink: https://cordis.europa.eu/project/id/INTAS-94-0905/de

European Union, 2024