Staroseletz Yaroslav, Gaponova Svetlana, Patutina Olga, Bichenkova Elena, Amirloo Bahareh, Heyman Thomas, Chiglintseva Daria, Zenkova Marina
Laboratory of Nucleic Acids Biochemistry, Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev's Ave. 8, 630090 Novosibirsk, Russia.
School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Rd., Manchester M13 9PT, UK.
Molecules. 2021 Mar 19;26(6):1732. doi: 10.3390/molecules26061732.
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)Gly] 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.
靶向RNA的治疗方法需要高效的序列特异性装置，能够在体内实现RNA的不可逆降解。目前，最成熟的序列特异性RNA切割方法，如小干扰RNA（siRNA）或反义寡核苷酸（ASO），都是基于招募细胞内的多蛋白复合物或酶，使得其他方法（如核酶和脱氧核酶）远远落后。最近，在单个分子支架中结合寡核苷酸识别基序（或其结构类似物）和催化活性基团的位点选择性人工核糖核酸酶已被证明是siRNA和ASO的有力竞争对手。一方面使用最有效的催化基团，包括依赖金属离子的（Cu（II）-2,9-二甲基菲咯啉）和无金属离子的（三（2-氨基苯并咪唑）），另一方面使用肽核酸（PNA）作为识别RNA的寡核苷酸，从而创建了半衰期为0.5-1小时的位点选择性人工核糖核酸酶。基于催化肽[（精氨酸-亮氨酸）-甘氨酸]的人工核糖核酸酶能够更进一步，它能够在肿瘤细胞中切割微小RNA-21（miRNA-21），并显著抑制小鼠肿瘤的生长。
