Oligonucleotide Based Artificial Ribonucleases (OBANs)

Ghidini, Alice; Murtola, Merita; Strömberg, Roger

doi:10.1002/9781118696880.ch3.2

Cited by 11 publications

(12 citation statements)

References 81 publications

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“…Metal ion-catalyzed cleavage of both RNA and DNA phosphodiester linkages has been investigated extensively to understand the mechanism of action of natural nucleases (including ribozymes) [1][2][3][4][5], as well as to develop artificial ones [6][7][8][9][10]. Comparative studies with phosphodiester and phosphorothioate model compounds have been instrumental in revealing coordination of catalytically important metal ions to the scissile linkage [11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Mercury(II)-Catalyzed Cleavage, Isomerization and Depurination of RNA and DNA Model Compounds and Desulfurization of Their Phosphoromonothioate Analogs

2020

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The potential of Hg(II), a metal ion so-far overlooked in the development of artificial nucleases, to cleave RNA and DNA has been assessed. Accordingly, Hg(II)-promoted cleavage and isomerization of the RNA model compound adenylyl-3′,5′-(2′,3′-O-methyleneadenosine) and depurination of 2′-deoxyadenosine were followed by HPLC as a function of pH (5.0–6.0) and the desulfurization of both diastereomers of the phosphoromonothioate analog of adenylyl-3′,5′-(2′,3′-O-methyleneadenosine) at a single pH (6.9). At 5 mM [Hg(II)], cleavage of the RNA model compound was accelerated by two orders of magnitude at the low and by one order of magnitude at the high end of the pH range. Between 0 and 5 mM [Hg(II)], the cleavage rate showed a sigmoidal dependence on [Hg(II)], suggesting the participation of more than one Hg(II) in the reaction. Isomerization and depurination were also facilitated by Hg(II), but much more modestly than cleavage, less than 2-fold over the entire pH range studied. Phosphoromonothioate desulfurization was by far the most susceptible reaction to Hg(II) catalysis, being accelerated by more than four orders of magnitude.

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Section: Introductionmentioning

confidence: 99%

Mercury(II)-Catalyzed Cleavage, Isomerization and Depurination of RNA and DNA Model Compounds and Desulfurization of Their Phosphoromonothioate Analogs

2020

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“…ON-based artificial nucleases (OBANs) [ 6 , 7 , 8 , 9 , 10 , 11 ] have the potential to affect RNA levels and thereby also diseases, while at the same time being independent of native enzymes with the freedom to use many available ON modifications. RNA sequence and secondary structures affect the reactivity of the phosphodiester bonds and studies have been done to evaluate structural parameters to support the development of sequence-specific RNA cleaving agents that mimic natural restriction enzymes [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Zinc Ion-Dependent Peptide Nucleic Acid-Based Artificial Enzyme that Cleaves RNA—Bulge Size and Sequence Dependence

et al. 2017

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In this report, we investigate the efficiency and selectivity of a Zn2+-dependent peptide nucleic acid-based artificial ribonuclease (PNAzyme) that cleaves RNA target sequences. The target RNAs are varied to form different sizes (3 and 4 nucleotides, nt) and sequences in the bulge formed upon binding to the PNAzyme. PNAzyme-promoted cleavage of the target RNAs was observed and variation of the substrate showed a clear dependence on the sequence and size of the bulge. For targets that form 4-nt bulges, we identified systems with an improved efficacy (an estimated half-life of ca 7–8 h as compared to 11–12 h for sequences studied earlier) as well as systems with an improved site selectivity (up to over 70% cleavage at a single site as compared to 50–60% with previous targets sequences). For targets forming 3-nt bulges, the enhancement compared to previous systems was even more pronounced. Compared to a starting point of targets forming 3-nt AAA bulges (half-lives of ca 21–24 h), we could identify target sequences that were cleaved with half-lives three times lower (ca 7–8 h), i.e., at rates similar to those found for the fastest 4-nt bulge system. In addition, with the 3-nt bulge RNA target site selectivity was improved even further to reach well over 80% cleavage at a specific site.

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“…Both methods are based on the recruitment of cellular enzymes by synthetic oligonucleotides. The promise to achieve comparable effects by conjugates of oligonucleotides with simple synthetic catalysts has stimulated the development of artificial nucleases [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Such compounds may also find some applications as tools for the chemical manipulation of RNA.…”

Section: Discussionmentioning

confidence: 99%

“…Synthetic nucleases used to cleave RNA in a sequence-specific manner are normally conjugates of a catalytic subunit and an oligonucleotide part required for substrate recognition via Watson-Crick base pairing [ 1 , 2 , 3 , 4 , 5 , 6 ]. Complexes of lanthanide ions have been most widely used as RNA cleavers [ 7 , 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Site-Specific Cleavage of RNAs Derived from the PIM1 3′-UTR by a Metal-Free Artificial Ribonuclease

et al. 2019

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Oligonucleotide conjugates of tris(2-aminobenzimidazole) have been reported previously to cleave complementary RNA strands with high levels of sequence and site specificity. The RNA substrates used in these studies were oligonucleotides not longer than 29-mers. Here we show that ~150–400-mer model transcripts derived from the 3′-untranslated region of the PIM1 mRNA reacted with rates and specificities comparable to those of short oligonucleotide substrates. The replacement of DNA by DNA/LNA mixmers further increased the cleavage rate. Tris(2-aminobenzimidazoles) were designed to interact with phosphates and phosphate esters. A cell, however, contains large amounts of phosphorylated species that may cause competitive inhibition of RNA cleavage. It is thus important to note that no loss in reaction rates was observed in phosphate buffer. This opens the way to in-cell applications for this type of artificial nuclease. Furthermore, we disclose a new synthetic method giving access to tris(2-aminobenzimidazoles) in multigram amounts.

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Oligonucleotide Based Artificial Ribonucleases (OBANs)

Cited by 11 publications

References 81 publications

Mercury(II)-Catalyzed Cleavage, Isomerization and Depurination of RNA and DNA Model Compounds and Desulfurization of Their Phosphoromonothioate Analogs

Mercury(II)-Catalyzed Cleavage, Isomerization and Depurination of RNA and DNA Model Compounds and Desulfurization of Their Phosphoromonothioate Analogs

Zinc Ion-Dependent Peptide Nucleic Acid-Based Artificial Enzyme that Cleaves RNA—Bulge Size and Sequence Dependence

Site-Specific Cleavage of RNAs Derived from the PIM1 3′-UTR by a Metal-Free Artificial Ribonuclease

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