Novel Bisimidazole-Containing Peptidomimetic Molecules for Мetal-Independent RNA Cleavage: Synthesis and Solid-Phase Screening Method

  • 4 Accesses


Novel bisimidazole-containing peptidomimetic molecules, which can efficiently cleave RNA in the absence of divalent metal ions have been synthesized. The thymidine 5'-monophosphate derivatives modified with these peptidomimetics have been obtained on CPG (controlled pore glass) using a solid phase azide-alkyne cycloaddition. The ability of all synthesized derivatives to cleave RNA has been demonstrated by a solid-phase screening method. The resulting conjugates have provided a 20–100% cleavage of the RNA target in 18 hours. The results allow us to consider the described strategy as a useful approach for the rapid selection of potentially promising peptidomimetic molecules in order to synthesize reactive constructs on their basis.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Fig. 1.
Fig. 2.


  1. 1

    Vlassov, V.V., Zuber, J., Felden, B., Behr, J.-P., and Giege, R., Nucleic Acids Res., 1995, vol. 23, pp. 3161–3167.

  2. 2

    Beloglazova, N.G., Tamkovich, N.V., Nikitin, P.A., Kuznetsova, I.L., Zenkova, M.A., and Vlasov, V.V., Vestn.VOGiS, 2006, vol. 10, pp. 382–394.

  3. 3

    Niittymaki, T. and Lönnberg, H., Org. Biomol. Chem., 2006, vol. 4, pp. 15–25.

  4. 4

    Lönnberg, H., Org. Biomol. Chem., 2011, vol. 9, pp. 1687–1703.

  5. 5

    Tamkovich, N., Koroleva, L., Kovpak, M., Goncharova, E., Silnikov, V., Vlassov, V., and Zenkova, M., Bioorg. Med. Chem., 2016, vol. 24, pp. 1346–1355.

  6. 6

    Fedorova, A.A., Goncharova, E.P., Koroleva, L.S., Burakova, E.A., Ryabchikova, E.I., Bichenkova, E.V., Silnikov, V.N., Vlassov, V.V., and Zenkova, M.A., Antivir. Res., 2016, vol. 133, pp. 73–84.

  7. 7

    Beloglazova, N.G., Fabani, M.M., Polushin, N.N., Sil’nikov, V.V., Vlassov, V.V., Bichenkova, E.V., and Zenkova, M.A., J. Nucleic Acids, 2011, pp. 1–17.

  8. 8

    Patutina, O.A., Bichenkova, E.V., Miroshnichenko, S.K., Mironova, N.L., Trivoluzzi, L.T., Burusco, K.K., Bryce, R.A., Vlassov, V.V., and Zenkova, M.A., Biomaterials, 2017, vol. 122, pp. 163–178.

  9. 9

    Patutina, O.A., Bazhenov, M.A., Miroshnichenko, S.K., Mironova, N.L., Pyshnyi, D.V., Vlassov, V.V., and Zenkova, M.A., Sci. Rep., 2018, vol. 8, no. 1, p. 14 990.

  10. 10

    Gurav, B. and Srinivasan, G., Curr. Sci., 2017, vol. 112, pp. 490–498.

  11. 11

    Sidorov, A.V., Grasby, J.A., and Williams, D.M., Nucleic Acids Res., 2004, vol. 32, pp. 1591–1601.

  12. 12

    Gnaccarini, C., Peter, S., Scheffer, U., Vonhoff, S., Klussmann, S., and Gobel, M.W., J. Am. Chem. Soc., 2006, vol. 128, pp. 8063–8067.

  13. 13

    Danneberg, F., Ghidini, A., Dogandzhiyski, P., Kalden, E., Strömberg, R., and Göbel, M.W., Beilstein J. Org. Chem., 2015, vol. 11, pp. 493–498.

  14. 14

    Wang, Y., Liu, E., Lam, C.H., and Perrin, D.M., Chem. Sci., 2018, vol. 9, pp. 1813–1821.

  15. 15

    Breslow, R., Acc. Chem. Res., 1991, vol. 24, pp. 317–324.

  16. 16

    Raines, R.T., Chem. Rev., 1998, vol. 98, pp. 1045–1065.

  17. 17

    Podyminogin, M.A., Vlassov, V.V., and Giege, R., Nucleic Acids Res., 1993, vol. 21, pp. 5950–5956.

  18. 18

    Silnikov, V., Zuber, G., Behr, J.-P., Giege, R., and Vlassov, V., Phosphorus Sulfur Silicon, 1996, vol. 109, pp. 277–280.

  19. 19

    Vlassov, V., Abramova, T., Godovikova, T., Giege, R., and Silnikov, V., Antisense Nucleic Acids Drug Dev., 1997, vol. 7, pp. 39–42.

  20. 20

    Yurchenko, L., Silnikov, V., Godovikova, T., Shishlan, G., Toulme, J.-J., and Vlassov, V., Nucleosides Nucleotides Nucleic Acids, 1997, vol. 16, pp. 1721–1725.

  21. 21

    Tornøe, C.W., Christensen, C., and Meldal, M., Org. Chem., 2002, vol. 67, pp. 3057–3064.

  22. 22

    Rostovtsev, V.V., Green, L.G., Fokin, V.V., and Sharpless, K.B., Angew. Chem., Int. Ed. Engl., 2002, vol. 41, pp. 2596–2599.

  23. 23

    Huisgen, R., Angew. Chem., Int. Ed. Engl., 1963, vol. 2, pp. 565–598.

  24. 24

    Huisgen, R., Angew. Chem., Int. Ed. Engl., 1963, vol. 2, pp. 633–645.

  25. 25

    Chan, T.R., Hilgraf, R., Sharpless, K.B., and Fokin, V.V., Org. Lett., 2004, vol. 6, pp. 2853–2855.

  26. 26

    Lewis, W.G., Magallon, F.G., Fokin, V.V., and Finn, M.G., J. Am. Chem. Soc., 2004, vol. 126, pp. 9152–9153.

  27. 27

    Gupta, S.S., Kuzelka, J., Singh, P., Lewis, W.G., Manchester, M., and Finn, M.G., Bioconjugate Chem., 2005, vol. 16, pp. 1572–1579.

  28. 28

    Kennedy, D.C., McKay, C.S., Legault, M.C., Danielson, D.C., Blake, J.A., Pegoraro, A.F., Stolow, A., Mester, Z., and Pezacki, J.P., J. Am. Chem. Soc., 2011, vol. 133, pp. 17 993–18 001.

  29. 29

    Amblard, F., Cho, J.H., and Schinazi, R.F., Chem. Rev., 2009, vol. 109, pp. 4207–4220.

  30. 30

    Ustinov, A.V., Stepanova, I.A., Dubnyakova, V.V., Zatsepin, T.S., Nozhevnikova, E.V., and Korshun, V.A., Russ. J. Bioorg. Chem., 2010, vol. 36, pp. 401–445.

  31. 31

    Severov, V.V., Varizhuk, A.M., and Pozmogova, G.E., Efferent. Fiz.-Khim. Med., 2012, vol. 1, pp. 10–16.

  32. 32

    Duan, Q., Lu, K., Ma, L., and Zhao, D., Nucleosides Nucleotides Nucleic Acids, 2015, vol. 34, pp. 579–589.

  33. 33

    Castro, V., Rodriguez, H., and Albericio, F., ACS Comb. Sci., 2016, vol. 18, pp. 1–14.

  34. 34

    Wenska, M., Alvira, M., Steunenberg, P., Stenberg, Å., Murtola, M., and Strömberg, R., Nucleic Acids Res., 2011, vol. 39, pp. 9047–9059.

  35. 35

    Hansen, M.B., van Gurp, T.H., van Hest, J.C., and Löwik, D.W., Org. Lett., 2012, vol. 14, pp. 2330–2333.

  36. 36

    Agouram, N., El Hadrami, E.M., Ben Tama, A., Julve, M., Anane, H., and Stiriba, S.-E., Der Pharma Chemica, 2016, vol. 8, pp. 499–506.

  37. 37

    Taskova, M., Madsen, C.S., Jensen, K.J., Hansen, L.H., Vester, B., and Astakhova, K., Bioconjugate Chem., 2017, vol. 28, pp. 768–774.

  38. 38

    Gershkovich, A.A. and Kibirev, V.K., in Sintez peptidov. Reagenty i metody (Peptide Synthesis: Reagents and Methods), Kiev: Naukova Dumka, 1987.

  39. 39

    Kelemen B.R., Klink, T.A., Behlke, M.A., Eubanks, S.R., Leland, P.A., and Raines, R.T., Nucleic Acids Res., 1999, vol. 27, pp. 3696–3701.

  40. 40

    Raines, R.T., in Artificial Nucleases, Zenkova, M., Ed., Berlin: Springer-Verlag, 2004, pp. 19–32.

  41. 41

    Wu, T.-P., Ruan, K.-C., and Liu, W.-Y., Nucleic Acids Res., 1996, vol. 24, pp. 3472–3473.

  42. 42

    Mironova, N.L., Pyshnyi, D.V., Shtadler, D.V., Fedorova, A.A., Vlassov, V.V., and Zenkova, M.A., Nucleic Acids Res., 2007, vol. 35, pp. 2356–2367.

  43. 43

    Seo, T.S., Li, Z., Ruparel, H., and Ju, J., Org. Chem., 2003, vol. 68, pp. 609–612.

  44. 44

    Parrish, B. and Emrick, T., Bioconjugate Chem., 2007, vol. 18, pp. 263–267.

  45. 45

    Vasilyeva, S.V., Silnikov, V.N., Shatskaya, N.V., Levina, A.S., Repkova, M.N., and Zarytova, V.F., Bioorg. Med. Chem., 2013, vol. 21, pp. 703–711.

  46. 46

    Horatscheck, A., Wagner, S., Ortwein, J., Kim, B.G., Lisurek, M., Beligny, S., Schütz, A., and Rademann, J., Angew. Chem., Int. Ed. Engl., 2012, vol. 51, pp. 9441–9447.

  47. 47

    Handbook of Biochemistry and Molecular Biology: Nucleic Acids, Fasman, T.E., Ed., Cleveland: CRC Press, 1975, vol. 1.

Download references


The authors thank N.L. Mironova (Laboratory of Biochemistry of Nucleic Acids (ICBFM, SB RAS)) for kindly providing RNase T1, M.F. Kasakin (Center of the Collective Use (ICBFM, SB RAS)) for recording mass spectra of the peptidomimetics and their derivatives.


The work was supported by the project no. A-0309-2016-0004.

Author information

Correspondence to D. V. Pyshnyi.

Ethics declarations


This article does not contain any studies with the use of humans and animals as objects of research.

Conflict of Interests

The authors state that there is no conflict of interests.

Additional information

Translated by A. Levina

Abbreviations: CPG, controlled pore glass; NA, nucleic acids; aRNase, artificial (synthetic) ribonuclease; miRNA, microRNA, special RNA molecules with a length of 19–25 nucleotides that are involved in transcription and posttranscription regulation of gene expression through RNA interference; piRNA or piwiRNA, special RNA molecules with a length of 24–30 nucleotides that interact with the PIWI protein complex and are involved in the inhibition of the activity of mobile genetic elements; CuAAC, azide-alkyne cycloaddition; TBTA, tris((1-benzyl-4-triazolyl)methyl)amine; BPS, bathophenanthroline disulfonate; THPTA, tris((1-hydroxypropyl-1H-1,2,3-triazol-4-yl)methyl)amine; RPC, reverse-phase chromatography; Flu, fluorescein residue; ТЕАА, triethylammonium acetate; BP, bromophenol blue; XC, xylene cyanole FF; ESI, electric field spray ionization.

A.S. Pavlova and P.A. Ogurtsova made an equal contribution to the work.

Corresponding author: phone: +7 (383) 363-51-51; fax: +7 (383) 363-51-53; e-mail:

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pavlova, A.S., Ogurtsova, P.A., Koroleva, L.S. et al. Novel Bisimidazole-Containing Peptidomimetic Molecules for Мetal-Independent RNA Cleavage: Synthesis and Solid-Phase Screening Method. Russ J Bioorg Chem 45, 813–824 (2019) doi:10.1134/S1068162019060311

Download citation


  • imidazole
  • azide-alkyne cycloaddition
  • artificial nucleases
  • RNA cleavage
  • solid-phase screening
  • CPG