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A Brief History of Genetic Therapy: Gene Therapy, Antisense Technology, and Genomics
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
A great deal of effort has been directed at understanding and modifying the stability, specificity and catalytic activity of trans-acting ribozymes by altering their nucleotide sequence, length and chemistry (Cech, 1992; Symons, 1992). The best characterized ribozyme is the hammerhead ribozyme; it is composed of two separate functional regions: a conserved catalytic core which cleaves the target RNA, and flanking regions, which are complementary to the target sequence and position the catalytic core for target cleavage. It is important to note that certain target sequences are not susceptible to ribozyme targeting because of sequence incompatibility; for hammerhead ribozymes, cleavage sites in most RNAs occur with a random frequency of 3/16 (Scanlon et al., 1995).
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Ribozymes (the name derives from a combination of “ribonucleic acid” and “enzyme”) are catalytic RNA molecules that can carry out specific biochemical reactions in a similar manner to protein-based enzymes. They are similar to antisense oligonucleotides in that they target and bind to complementary sequences of mRNA. Many ribozymes have either a hairpin or hammerhead form (Figure 5.96) with a shaped active center and a unique secondary structure that allows them to cleave other RNA molecules at specific sequences. Although isolated ribozymes are not common in cells, their roles are essential for some components of the cellular machinery. For example, the functional large subunit component of the ribosome, the molecular machine that translates RNA into proteins, is essentially a ribozyme composed of RNA tertiary structural motifs that can be coordinated to metal ions such as Mg2+ as cofactors. Molecular model of a hammerhead ribozyme (Taken from Wikipedia, “Minimal hammerhead ribozyme structure” by I, Wgscott, under the Creative Commons Attribution-Share Alike 3.0 Unported license (https://creativecommons.org/licenses/by-sa/3.0/legalcode)).
The discovery and development of RNA-based therapies for treatment of HIV-1 infection
Published in Expert Opinion on Drug Discovery, 2023
Michelle J Chen, Anne Gatignol, Robert J. Scarborough
The first anti-HIV-1 ribozyme results were published in 1990 using the small-self cleaving hammerhead ribozyme motif [42]. It was shown to cleave HIV-1 RNA in a cell-free system and in human cells when expressed from an artificial gene. Since then, several ribozymes have been designed to target various regions of HIV-1 RNA with most being designed for use in gene therapy (described in section 3.1). A few studies have explored the exogenous delivery of pre-synthesized anti-HIV-1 ribozymes for development as drugs. In one study, a ribozyme targeting the gag open reading frame of HIV-1 RNA was able to inhibit HIV-1 replication in a T lymphocyte cell line [43]. However, the ribozyme was quickly degraded with no ribozyme RNA detected 5 hours after delivery. In another study, a chimeric DNA/RNA ribozyme was delivered to HIV-1 infected cells by a variety of cationic liposome complexes [44]. They concluded that this method of administering functional ribozymes was inefficient and that delivery of ribozymes by gene therapy would be a more promising strategy for HIV-1 therapy.
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 hammerhead RNA is a single-stranded RNA motif that undergoes autocatalytic self-cutting, and because of its feature, it is not a real enzyme in the biological context [71]. The terms “hammerhead ribozyme” and “hammerhead RNA” can be used interchangeably [72]. The structure of hammerhead ribozymes consists of three helices called I, II and III attached to an 11-nucleotide length catalytic core. The catalytic core has a substrate recognition area containing two bodies on either side of the dividing region [73]. Hammerhead and hairpin ribozymes are small, sequence-specific RNA endonucleases. They can be manipulated easily for maintaining specificity and regulate catalytic activity [74]. However, a relatively insignificant small connection gains catalytic properties by removing the loop region from the strand and gives the ability to react with multiple substrates. Hammerhead ribozymes are the most remarkable catalytic RNA motifs for gene editing activities [75,76]. Besides, ribozymes have been frequently used in various viral inhibition studies [77–79].