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Novel dual inhibitors targeting HIV-1 integrase and reverse transcriptase-associated ribonuclease H activityтезисы доклада
- Авторы: Korolev S., Pustovarova M., Atrokhova A., Zhuze A., Gottikh M.
- Сборник: ВИЧ-инфекция и иммуносупрессии
- Том: 8
- Тезисы
- Год издания: 2016
- Место издания: Балтийский медицинский образовательный центр Санкт-Петербург
- Первая страница: 105
- Последняя страница: 105
- Аннотация: Reverse transcriptase (RT) and integrase (IN) facilitate the early stages of HIV-1 replication. HIV-1 integrase (IN) and reverse transcriptase (RT)-associated ribonuclease H (RNase H) domains belong to the polynucleotidyl transferase superfamily and share common structural features. The catalytic sites of both enzymes contain a central core composed of three highly conserved amino acid residues forming the DDE motif or RNase H-like fold (Asp, Asp and Glu). Among the novel approaches aimed to identify new HIV-1 inhibitors, the development of dual-action inhibitors, single drugs that may act on two different enzymes, such as IN and RNase H. A number of attempts has been made to identify compounds that may act on both enzymes, but still there is no dual inhibitor passed the clinical trials [Corona A., et al. Antomicrob. Agents Chemother., 2014, 58 (10), 6101-6110; Cuzzucolli Crucitti G., et al. J. Med. Chem., 2015, 58 (4), 1915-1928; Esposito F., et al. Antiviral Chem. Chemother., 2014, 23, 129-144]. In our previous works, we have studied in detail the integration inhibition by dimeric bis-benzimidazoles (DBI) [Zhuse A.L., et al. J. Biomol. Struct. Dyn., 2007, 24(6), 666-668; Korolev S.P., et al. Russian J. of Mol. Biol., 44 (4), 633-641.]. The inhibitory effect of these compounds are explainable by the fact that they interfere with a correct binding of the DNA substrate in the IN active center. To enable their potential use however requires to overcome their low solubility in water and to increase their bioavailability. Recently the new series of water soluble DBI has been obtained. The inhibitory activity of these compounds was determined for both recombinant enzymes IN and RNase H. It was shown that the inhibition ability for the set of compounds depends on the length of the spacer connecting the pairs of benzimidazole fragments. The IC50 values of the most active one were 50 nM for IN and 5 µM for RNase H. Moreover these compounds demonstrated extremely low cytotoxity (CC50 > 100µM). According to preliminary trials the most active DBI showed its inhibitor activity on replication-incompetent VSV-G-pseudotyped vector HIV-1 based. Overall, DBI may be considered as a potent dual-acting inhibitor for treatment of HIV-1 infections.
- Добавил в систему: Королев Сергей Павлович