HIV-1 integrase inhibition by dimeric bisbenzimidazoles with different spacer structures

Autor: Alexei L. Zhuze, A. V. Gromyko, Vadim N. Tashlitsky, Marina Gottikh, Yu. Yu. Agapkina, Maksim Smolov, S. P. Korolev
Rok vydání: 2010
Předmět:
Zdroj: Molecular Biology. 44:633-641
ISSN: 1608-3245
0026-8933
DOI: 10.1134/s0026893310040199
Popis: HIV-1 integrase is responsible for one of the key stages in virus replication, namely, integration of viral cDNA into the host cell genome. Integration inhibition leads to a complete block of the virus replication. We studied the integration inhibition by dimeric bisbenzimidazoles DBBI(7) with heptamethylene and DBBI(8) with tri(ethylene glycol) spacers and found that IC50 for DBBI(7) was approximately 0.03 μM and for DBBI(8) it was approximately 10 μM. Cross-linking assays demonstrated that both compounds interfered with a proper positioning of the DNA substrate in the active centre of integrase. To clarify the inhibition mechanism, dissociation constants were determined for the complexes between DBBI and integrase DNA substrate. Calculated K d values for the complexes formed by DBBI(7) and DBBI(8) were 270 and 140 nM, respectively. Thus, the integration inhibition is not directly connected with DBBI binding to DNA. The dependence of initial enzymatic reaction rate on DNA substrate concentration in the presence of different concentrations of inhibitors was found, and inhibition constants were determined. These data suggest that different inhibition activity of DBBI(7) and DBBI (8) is determined by different mechanisms underlying their action, namely, competitive inhibition of integrase by DBBI(7) and a more complex mechanism assumed for DBBI(8).
Databáze: OpenAIRE
Externí odkaz: