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Интеллектуальная Система Тематического Исследования НАукометрических данных |
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Telomerase is the key enzyme in the maintenance of telomere length connected to proliferative potential of the cell. Inhibition of the telomerase could be basis of an anti-cancer therapy for the ~90% of human tumors with activated telomerase whereas telomerase activity usually is undetectable in somatic cells. To search for new inhibitors of telomerase we were used two approaches. One is well-known approach based on the screening of small molecules and the other is a new approach for impairing telomerase function at the stage of human telomerase assembly with the application of chimeric bifunctional oligonucleotides. We tested a panel of new metalorganic compounds for telomerase inhibition and for cytotoxic effect. We have found that telomerase-inhibiting compound did not intercalate DNA, inhibited number of other polymerases, accumulated in the cell nucleus, and caused DNA degradation. Preliminary studies revealed that lead compound inhibited human breast adenocarcinoma growth in mice model. Chimeric bifunctional oligonucleotides for telomerase inhibition contain two oligonucleotide parts complementary to the functional domains of telomerase RNA connected with non-nucleotide linkers in different orientations (5'-3', 5'-5' or 3'-3'). Such chimeras inhibited telomerase in vivo in nM concentrations, predominantly due to their effect on telomerase assembly and dimerization. Chimeric bifunctional oligonucleotides for blocking assembly can be used to disrupt the function of any RNA-protein complexes.