[HIV-1 integrase inhibition by dimeric bisbenzimidazoles having different spacers].

HIV-1 integrase is responsible for one of the key steps of the viral replication, integration of the viral cDNA into the host cell genome. Integration inhibition leads to complete block of the virus replication. In this study inhibition of integration by dimeric bisbenzimidazoles DBBI(7) with heptamethylene and DBBI(8) with tri(ethylene glycol) spacers was examined, and it was learned out that IC50 for DBBI(7) was about 0.03 microM, and IC50 for DBBI(8) was about 10 microM. By using cross-linking assays, it was shown that both compounds impeded a proper disposition of DNA-substrate at the active centre of integrase. Dissociation constants for complexes between either DBBI and DNA-substrate of integrase were determined. Calculated Kd values were 270 nM and 140 nM for complexes formed by DBBI(7) and DBBI(8), respectively. Therefore, inhibition of integration does not directly result from the binding of DBBIs with DNA. The dependence of initial rates of enzymatic reaction on the DNA-substrate concentration in presence of different concentrations of inhibitors was found, and inhibition constants were determined. All the data obtained allow us to suppose that the different inhibition activity of DBBI(7) and DBBI(8) results from the different mechanism of their binding: DBBI(7) is a competitive inhibitor of integrase whereas DBBI(8) is assumed to show a more complex mechanism of inhibition.

Relative Comparison of Catalytic Characteristics of Human Foamy Virus and HIV-1 Integrases.

Due to their ability to integrate into the host cell's genome, retroviruses represent an optimal basis for the creation of gene therapy vectors. The integration reaction is carried out by a viral enzyme integrase: thus, a detailed research of this enzyme is required. In this work, the catalytic properties of human foamy virus integrase were studied. This virus belongs to the Retroviridae family. The dissociation constant was determined, together with the kinetics of integrase catalytic activity. The data obtained were compared to those for the human immunodeficiency virus integrase and a considerable similarity in the activity of the two enzymes was observed.