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

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Abstract

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.

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ACKNOWLEDGMENTS

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.

FUNDING

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

Author information

Correspondence to D. V. Pyshnyi.

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COMPLIANCE WITH ETHICAL STANDARDS

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

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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: pyshnyi@niboch.nsc.ru.

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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

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Keywords:

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