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Oligonucleotide inhibitors of HIV-1 integrase efficiently inhibit HIV-1 reverse transcriptase

Abstract

The impact of conjugates of 11-mer 2′-О-methyl oligoribonucleotides with eosin and 6-carboxy-4,7,2′,4′,5′,7′-hexachlorofluorescein on the functioning of HIV-1 reverse transcriptase (RT) was studied. These compounds were shown to inhibit the activity of RT RNase H domain. The inhibition efficiency was higher for eosin conjugates and did not depend on the oligonucleotide primary structure. The eosin conjugates were also found to block the RT polymerase activity including the mutant proteins resistant to nonnucleoside inhibitors. Since the conjugates are efficient inhibitors of HIV-1 integrase, we can assume that they belong to a new class of HIV-1 dual acting inhibitors, potentially capable of blocking several initial stages of the viral replication cycle.

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Abbreviations

AIDS:

acquired immune deficiency syndrome

Dd:

DNA-dependent

HEX:

6-carboxy-4,7,2′,4′,5′,7′-hexachlorofluorescein

HIV:

human immunodeficiency virus

IN:

integrase

Rd:

RNA-dependent

RT:

reverse transcriptase

References

  1. Solomon, D.A. and Sax, P.E., Curr. Opin. HIV AIDS, 2015, vol. 10, no. 4, pp. 219–225.

    CAS  Article  PubMed  Google Scholar 

  2. Andréola, M.L., Curr. Pharm. Des., 2004, vol. 10, no. 30, pp. 3713–3723.

    Article  PubMed  Google Scholar 

  3. Esposito, F. and Tramontano, E., Antivir. Chem. Chemother., 2014, vol. 23, no. 4, pp. 129–144.

    Article  PubMed  Google Scholar 

  4. Davies, J.F., II., Hostomska, Z., Hostomsky, Z., Jordan, S.R., and Matthews, D.A., Science, 1991, vol. 252, pp. 88–95.

    CAS  Article  PubMed  Google Scholar 

  5. Esposito, D. and Craigie, R., Adv. Virus Res., 1999, vol. 52, pp. 319–333.

    CAS  Article  PubMed  Google Scholar 

  6. Cirino, N.M., Cameron, C.E., Smith, J.S., Rausch, J.W., Roth, M.J., Benkovic, S.J., and Le Grice, S.F., Biochemistry, 1995, vol. 34, pp. 9936–9943.

    CAS  Article  PubMed  Google Scholar 

  7. Leh, H., Brodin, P., Bischerour, J., Deprez, E., Tauc, P., Brochon, J.C., LeCam, E., Coulaud, D., Auclair, C., and Mouscadet, J.F., Biochemistry, 2000, vol. 39, pp. 9285–9294.

    CAS  Article  PubMed  Google Scholar 

  8. Billamboz, M., Bailly, F., Lion, C., Touati, N., Vezin, H., Calmels, C., Andréola, M.L., Christ, F., Debyser, Z., and Cotelle, P., J. Med. Chem., 2011, vol. 54, no. 6, pp. 1812–1824.

    CAS  Article  PubMed  Google Scholar 

  9. Cuzzucoli Crucitti, G., Métifiot, M., Pescatori, L., Messore, A., Madia, V.N., Pupo, G., Saccoliti, F., Scipione, L., Tortorella, S., Esposito, F., et al., J. Med. Chem., 2015, vol. 58, no. 4, pp. 1915–1928.

    CAS  Article  PubMed  Google Scholar 

  10. Didierjean, J., Isel, C., Querré, F., Mouscadet, J.F., Aubertin, A.M., Valnot, J.Y., Piettre, S.R., and Marquet, R., Antimicrob. Agents Chemother., 2005, vol. 49, no. 12, pp. 4884–4894.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Billamboz, M., Bailly, F., Barreca, M.L., De Luca, L., Mouscadet, J.F., Calmels, C., Andréola, M.L., Witvrouw, M., Christ, F., Debyser, Z., et al., J. Med. Chem., 2008, vol. 51, no. 24, pp. 7717–7730.

    CAS  Article  PubMed  Google Scholar 

  12. Costi, R., Métifiot, M., and Esposito, F., Cuzzucoli Crucitti G., Pescatori L., Messore A., Scipione L., Tortorella S., et al., J. Med. Chem., 2013, vol. 56, no. 21, pp. 8588–8598.

    CAS  Article  PubMed  Google Scholar 

  13. De Soultrait, V.R., Lozach, P.Y., Altmeyer, R., Tarrago-Litvak, L., Litvak, S., and Andréola, M.L., J. Mol. Biol., 2002, vol. 324, no. 2, pp. 195–203.

    Article  PubMed  Google Scholar 

  14. Prokofjeva, M.M., Spirin, P.V., Yanvarev, D.V., Ivanov, A.V., Novikov, M.S., Stepanov, O.A., Gottikh, M.B., Kochetkov, S.N., et al., Acta Naturae, 2011, vol. 3, no. 4, pp. 55–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Anisenko, A., Agapkina, J., Zatsepin, T., Yanvarev, D., and Gottikh, M., Biochimie, 2012, vol. 94, pp. 2382–2390.

    CAS  Article  PubMed  Google Scholar 

  16. Agapkina, J., Yanvarev, D., Anisenko, A., Korolev, S., Vepsalainen, J., Kochetkov, S., and Gottikh, M., Eur. J. Med. Chem., 2014, vol. 73, pp. 73–82.

    CAS  Article  PubMed  Google Scholar 

  17. Song, Y., Chan, J.M., Tovian, Z., Secrest, A., Nagy, E., Krysiak, K., Bergan, K., Parniak, M.A., and Oldfield, E., Bioorg. Med. Chem., 2008, vol. 16, pp. 8959–8967.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Gromyko, A.V., Salyanov, V.I., Strel’tsov, S.A., Oleinikov, V.A., Korolev, S.P., Gottikh, M.B., and Zhuze, A.L., Russ. J. Bioorg. Chem., 2007, vol. 33, no. 6, pp. 569–578.

    CAS  Article  Google Scholar 

  19. Korolev, S.P., Tashlitsky, V.N., Smolov, M.A., Gromyko, A.V., Zhuze, A.L., Agapkina, Yu.Yu., and Gottikh, M.B., Mol. Biol., 2010, vol. 44, pp. 633–641.

    CAS  Article  Google Scholar 

  20. Pinskaya, M., Romanova, E., Volkov, E., Deprez, E., Leh, H., Brochon, J.-C., Mouscadet, J.-F., and Gottikh, M., Biochemistry, 2004, vol. 43, pp. 8735–8743.

    CAS  Article  PubMed  Google Scholar 

  21. Agapkina, J., Zatsepin, T., Knyazhanskaya, E., Mouscadet, J.-F., and Gottikh, M., ACS Med. Chem. Lett., 2011, vol. 2, pp. 532–537.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Huang, H., Chopra, R., Verdine, G.L., and Harrison, S.C., Science, 1998, vol. 282, pp. 1669–1675.

    CAS  Article  PubMed  Google Scholar 

  23. Korolev, S., Knyazhanskaya, E., Anisenko, A., Tashlitsky, V., Zatsepin, T.S., Gottikh, M., and Agapkina, J., Nucleosides Nucleotides Nucleic Acids, 2011, vol. 30, pp. 651–666.

    CAS  Article  PubMed  Google Scholar 

  24. Das, K. and Arnold, E., Curr. Opin. Virol., 2013, vol. 3, no. 2, pp. 119–128.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Novikov, M.S., Ivanova, O.N., Ivanov, A.V., Ozerov, A.A., Valuev-Elliston, V.T., Temburnikar, K., Gurskaya, G.V., Kochetkov, S.N., and Pannecouque, C., Bioorg. Med. Chem., 2011, vol. 19, no. 19, pp. 5794–5802.

    CAS  Article  PubMed  Google Scholar 

  26. Le Grice, S.F. and Grüninger-Leitch, F.R, Eur. J. Biochem., 1990, vol. 187, no. 2, pp. 307–314.

    Article  PubMed  Google Scholar 

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Correspondence to S. P. Korolev.

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Original Russian Text © S.P. Korolev, T.S. Zatsepin, M.B. Gottikh, 2017, published in Bioorganicheskaya Khimiya, 2017, Vol. 43, No. 2, pp. 157–162.

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Korolev, S.P., Zatsepin, T.S. & Gottikh, M.B. Oligonucleotide inhibitors of HIV-1 integrase efficiently inhibit HIV-1 reverse transcriptase. Russ J Bioorg Chem 43, 135–139 (2017). https://doi.org/10.1134/S1068162017020078

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  • DOI: https://doi.org/10.1134/S1068162017020078

Keywords

  • HIV-1
  • oligonucleotide inhibitors
  • reverse transcriptase
  • RNase H