title: Modulation of HIV-1 integrase activity by single-stranded oligonucleotides and their conjugates with eosin.
abstract: Integration of the DNA copy of the genomic RNA into an infected cell genome is one of the key steps of the replication cycle of all retroviruses. It is catalyzed by the viral enzyme, integrase. We have shown that conjugates of short single-stranded oligonucleotides with eosin efficiently inhibit the catalytic activity of the HIV-1 integrase. In this article, we have found that the dependence of the integrase catalytic activity on the concentration of oligonucleotides has a bell-shaped pattern. The modulation of HIV-1 integrase activity correlated with the oligonucleotide length and was not associated with specific sequences. Moreover, a similar mode of the oligonucleotide action was found for integrase from the prototype foamy virus. This dual effect of the oligonucleotide and their conjugates with eosin might be explained by their binding with retroviral integrase in two different sites; the oligodeoxynucleotide binding in the first site results in integrase activation, whereas interactions with another one lead to inhibition of the enzyme activity. Eosin coupling to oligonucleotides did not change the mode of their action but enhanced their affinity to both binding sites. The affinity increase was found to be much more important for the site responsible for the integrase inhibition, thus explaining the high inhibitory potency of oligonucleotide-eosin conjugates.
authors: Department of Chemistry, Belozersky Institute of Physical and Chemical Biology, Moscow State University, Moscow, Russia.
authors: Sergey
authors: S
authors: Korolev
authors: Ekaterina
authors: E
authors: Knyazhanskaya
authors: Andrey
authors: A
authors: Anisenko
authors: Vadim
authors: V
authors: Tashlitskii
authors: Timofei S
authors: TS
authors: Zatsepin
authors: Marina
authors: M
authors: Gottikh
authors: Julia
authors: J
authors: Agapkina
mesh_terms: D004801:Eosine Yellowish-(YS) / Q000737:chemistry* / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D009841:Oligonucleotides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D019428:HIV Integrase Inhibitors; D009841:Oligonucleotides; D019427:HIV Integrase; D004801:Eosine Yellowish-(YS); C514801:p31 integrase protein, Human immunodeficiency virus 1