Site-Selective Artificial Ribonucleases: Renaissance of Oligonucleotide Conjugates for Irreversible Cleavage of RNA Sequences

Abstract

RNA-targeting therapeutics require highly efficient sequence-specific devices capable of RNA irreversible degradation in vivo. The most developed methods of sequence-specific RNA cleavage, such as siRNA or antisense oligonucleotides (ASO), are currently based on recruitment of either intracellular multi-protein complexes or enzymes, leaving alternative approaches (e.g., ribozymes and DNAzymes) far behind. Recently, site-selective artificial ribonucleases combining the oligonucleotide recognition motifs (or their structural analogues) and catalytically active groups in a single molecular scaffold have been proven to be a great competitor to siRNA and ASO. Using the most efficient catalytic groups, utilising both metal ion-dependent (Cu(II)-2,9-dimethylphenanthroline) and metal ion-free (Tris(2-aminobenzimidazole)) on the one hand and PNA as an RNA recognising oligonucleotide on the other, allowed site-selective artificial RNases to be created with half-lives of 0.5–1 h. Artificial RNases based on the catalytic peptide [(ArgLeu)2Gly]2 were able to take progress a step further by demonstrating an ability to cleave miRNA-21 in tumour cells and provide a significant reduction of tumour growth in mice.

Influence of sequence variation on the RNA cleavage activity of Zn2+-dimethyl-dppz-PNA-based artificial enzymes

“…2,3 The development of efficient articial enzymes capable of sequence-specic cleavage of RNA has been a long-standing goal of nucleic acid chemistry. [4][5][6][7][8] Such articial ribonucleases have the potential to achieve degradation of disease-related RNA targets without the assistance of endogenous enzymes, thereby offering an alternative to gapmer antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), 3,9 both of which are used in the clinic today.…”

Topical Application of Peptide Nucleic Acid Antisense Oligonucleotide for MMP-1 and Its Potential Anti-Aging Properties

“…Antisense oligonucleotides (ASO) can also bind to a pre-mRNA in the nucleus and affect the splicing of the pre-mRNA, producing an altered mRNA sequence [ 17 , 18 ]. However, one of the main barriers in applying ASO technology is the rapid degradation of DNA-based oligonucleotides in cells by nucleases [ 19 ].…”

Organometallic modification confers oligonucleotides new functionalities

“…Given the programmable sequence recognition properties, the most obvious and also the most extensively studied use for oligonucleotide catalysts is the cleavage of other nucleic acids. [185][186][187][188][189][190][191] Efficient artificial nucleases are accessible through the simple and modular approach of covalently tethering a cleaving agent to a guiding oligonucleotide strand. Alternatively, catalytic oligonucleotides can be found through an iterative process known as systematic evolution of ligands by exponential enrichment (SELEX).…”