Sugar and Base-Modified 2′,3′-Dideoxynucleosides as Potential Anti-Aids Drugs

Abstract

Several 2′,3′-dideoxynucleosides have proven to be effective against HIV-1 in cell culture. The 2′,3-unsaturated analogues dideoxycytidinene (D4C) and dideoxythymidinene (D4T) are among the most potent and selective inhibitors of HIV-1 replication in vitro. However, 2′,3′-didehydro-2′,3′-dideoxynucleosides are relatively unstable. A chlorine substituent at the 2′-position increases the stability, and, therefore, some 2′-chloro-2′,3′-didehydro-2′,3′-dideoxynucleosides were synthesized and evaluated for anti-HIV-1 activity.     

Modulation of HIV-1 integrase activity by single-stranded oligonucleotides and their conjugates with eosin

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.     

Design and synthesis of N1-aryl-benzimidazoles 2-substituted as novel HIV-1 non-nucleoside reverse transcriptase inhibitors

A series of novel N₁-aryl-2-arylthioacetamido-benzimidazoles were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Some of them proved to be effective in inhibiting HIV-1 replication at submicromolar and nanomolar concentration acting as HIV-1 non-nucleoside RT inhibitors (NNRTIs), with low cytotoxicity. The preliminary structure–activity relationship (SAR) of these new derivatives was discussed and rationalized by docking studies.