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Upon HIV-1 infection of a target cell, viral reverse transcriptase (RT) copies the genomic RNA to synthesize the viral DNA. Then viral integrase (IN) catalyzes insertion of the viral DNA into infected cell genome. Inhibition of the activity of these proteins should completely block vital activity of the virus right after the infection. New and effective drugs against HIV-1 continue to be required, which prompted us to search for compounds aimed at inhibiting both RT and IN. We studied the effect of short single-strand oligonucleotides conjugated with hydrophobic molecules on the IN and RT catalytic activities. Step-by-step modifications in both oligonucleotide and hydrophobic parts of the conjugate were carried out and the modification influence on the inhibitory effect was determined. Both parts of the conjugate, oligonucleotide and hydrophobic, was found to play an important role in the inhibition of both RT and IN. The oligonucleotide conjugates with 2,4,5,7-tetrabromofluoresceine (eosin) were found to be the most efficient inhibitors of IN (IC50 =50 nM); they also inhibited the activity of RT-associated RNase H at submicromolar concentrations. The inhibitors were still active against several RT mutants possessing resistance to non-nucleoside inhibitors (K103N/Y181C, V106A, Y188L) and IN mutants resistant to the strand transfer inhibitors (E92Q, G140S/Q148K and N155H). The ability of the conjugates to block a direct binding of RT and IN was also studied. Being delivered intracellularly using a cell-penetrating-peptide, the conjugates were found to impede HIV-1 replication at nanomolar concentrations. Extensive analysis showed that viral cDNA synthesis was severely impaired by mODNs. The work was supported by RFBR (grants 11-04-01004 and 12-04-30-mol_a).