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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Once bound to their target RNA, ribozymes elicit cleavage of the bound mRNA fragment by invoking the RNase H enzyme (Figure 5.97). Unlike antisense oligonucleotides, the unique base-pair sequence of a ribozyme allows it to adopt the shape of either a hairpin or a hammerhead, which gives rise to the main way of categorizing ribozymes.Mechanism of RNA cleavage by a hairpin ribozyme.
Non-VLPs
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Although the MS2 name was still dominant in the 1990s, some studies retained the traditional early R17 name in the tethering studies at that time. Thus, Han et al. (1992) and Newstein et al. (1993) reported that they constructed chimeric HIV-1 TAR sequences that contained the R17 RNA sequence and a fusion of the Tat protein with the MS2 coat. The R17 platform was used when the gel retardation assays were performed to compare the R17 coat-RNA and the HIV Tat-TAR interactions (Pearson et al. 1994). The R17 hairpin was linked to the ribozyme helix 4, which lies at the periphery of the catalytic domain (Sargueil et al. 1995). In the absence of the MS2 coat, the incorporation of the R17 hairpin increased the catalytic efficiency of the hairpin ribozyme by 2-fold for the cleavage reaction and 16-fold for the ligation reaction. The kinetics of cleavage and ligation reactions were not altered by the presence of saturating concentrations of coat protein, while the coat protein remained bound to the ribozyme throughout the catalytic cycle (Sargueil et al. 1995).
Virus-associated ribozymes and nano carriers against COVID-19
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2021
Beyza Dönmüş, Sinan Ünal, Fatma Ceren Kirmizitaş, Nelisa Türkoğlu Laçin
The hairpin ribozymes are called due to their shape resembling a hairpin. They catalyse a reversible cleavage reaction that produces 2′,3′-cyclic phosphate, and 5′-hydroxyl tip, like other self-cutting small ribozymes. First, it was observed that the tobacco ring stain virus was found in the negative strand of the satellite RNA [89]. Although self-cutting small ribozyme motifs can catalyse the same chemical reactions, all these small ribozymes adopt a different structure and use a different catalytic mechanism. The hairpin ribozyme, unlike others, is unique in not requiring direct coordination of metal cations with phosphate or water oxygen for cleavage and ligation reactions. The functional groups in the motif itself carry out the reaction. Despite the importance of this functional group in the hairpin ribozyme was not determined in the first years. The necessity of G8 nucleobase for catalytic activity was found in the following years [90]. In the secondary structure of the hairpin ribozyme, it contains five loops separated by four paired spirals from H1 to H4 [91]. Thus, the shape of the ribozyme can be divided into two domains. Domain 1: besides the spiral 1 and 2, the loop covers 1 and 5, while domain 2: contains the spiral 3 and 4, the loop consists of 2, 3 and 4. The formation of the helical 1 and 2 between the ribozyme and the substrate as the catalytic zone allows the formation of two symmetrical loops directly to each other. The other three loops remain inside the ribozyme due to coils 3 and 4. The entire complex consists of 18 base pairs with non-standard A:G matching [92]. Targeting with hairpin ribozyme requires the BN * GUC gene sequence and match the bases between helical 1 and 2. The base shown as B can be G, U or C, but it should not be A (Figure 5). In a study, it was determined that the substrate cutting reaction does not occur with A base [91]. Also, hairpin ribozyme has been proven in previous studies to suppress gene regulation in hepatitis C, hepatitis B and human papillomavirus [93].