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Introduction to Cells, DNA, and Viruses
Published in Patricia G. Melloy, Viruses and Society, 2023
When it comes to the classifications of animal viruses, all roads lead to a functional mRNA product. The initial classes were labeled I–VI, with a seventh category added later (Baltimore 1971; Summers 2009; Lostroh 2019). Class I contains viruses with a double-stranded DNA viral genome. Class II contains viruses with a single-stranded DNA genome. This single strand happens to be a “+ strand” of DNA, meaning that it is the “sense” strand, equivalent to the mRNA product except for thymidine being replaced with uracil. Class III has viruses with a double-stranded RNA genome. Class IV contains viruses with a + strand, single-stranded RNA genome. Class V contains viruses with a single-stranded RNA genome that is the “− strand,” or antisense strand, being the opposite polarity of the mRNA. Class VI and VII are related in that a nucleic acid intermediate has been found between the viral genome and the mRNA product. In Class VI, there is a DNA intermediate for a single-stranded RNA genome of the sense orientation. In Class VII, there is a DNA intermediate for a double-stranded DNA genome (Summers 2009; Baltimore 1971).
SARS-CoV-2 Morphology, Genomic Organisation and Lifecycle
Published in Srijan Goswami, Chiranjeeb Dey, COVID-19 and SARS-CoV-2, 2022
Srijan Goswami, Ushmita Gupta Bakshi
But if the translation process while proceeding through OFR1a frameshifts to a region of ORF1b, the resultant protein thus formed is pp1ab. Polyprotein 1ab is the hybrid of ORF1a and ORF1b. These polyproteins are further proteolyzed into numerous smaller proteins and play a critical role in viral replication and transcription. Proteins involved in replication are called replicase complex while the proteins involved in transcription are called transcriptase complex. All these proteins combine with viral genomic RNA (sense strand) and facilitate replication. When the +ssRNA of the coronavirus replicates, an antisense RNA is produced. The conversion of the sense RNA into antisense RNA is very much important for the lifecycle of the virus. The antisense RNA is important because:It can be replicated back to sense RNA, which is essentially the same thing that entered with the original virus during uncoating.This antisense RNA can be transcribed through a method called discontinuous transcription. Discontinuous transcription of antisense RNA generates a diverse range of mRNAs that can then be translated into different proteins.
The Emerging Field of RNA Nanotechnology
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Small interfering RNA [42, 44] (siRNA) is a helix with 20–25 nucleotides that interferes with gene expression through the cleavage of mRNA by a protein/RNA complex named RISC (RNA-induced silencing complex). The siRNA specifically suppresses the expression of a target protein whose mRNA includes a sequence identical to the sense strand of the siRNA. The discovery led to the award of the 2006 Nobel Prize to Andrew Fire and Craig Mello [42].
Clinical pharmacology of siRNA therapeutics: current status and future prospects
Published in Expert Review of Clinical Pharmacology, 2022
Ahmed Khaled Abosalha, Jacqueline Boyajian, Waqar Ahmad, Paromita Islam, Merry Ghebretatios, Sabrina Schaly, Rahul Thareja, Karan Arora, Satya Prakash
Simply, siRNAs are designed to block the expression of targeted genes at the post-transcriptional stage by degrading the mRNA that governs the regulation of these genes. Therefore, siRNAs are designated as small double-stranded RNA duplexes with a 21–23 nucleotide length. One strand of this duplex is complementary to the mRNA of the gene of interest and known as the ‘guiding’ or ‘antisense’ strand. This guiding strand can easily and specifically recognize the mRNA of the targeted gene and degrade it, a process known as ‘gene silencing.’ Gene silencing begins when a long double-stranded RNA (dsRNA) is cleaved by a specific dicer enzyme, a member of the RNAase family, into short siRNAs. Then, these siRNAs are incorporated into a multi-protein complex termed, ‘ (RISC).’ Subsequently, siRNA binds to argonaute-2 receptors, a crucial component of RISC, with a consequent cleavage of siRNA duplex into two strands: the passenger (sense) strand and the guiding strand. The sense strand is degraded while the guiding strand recognizes the complementary mRNA of the gene of interest and destroys it into numerous nonfunctional units. This process downregulates the expression of targeted genes and proteins as demonstrated in Figure 1 [29–32].
Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia
Published in Expert Opinion on Drug Safety, 2022
Yajnavalka Banerjee, Anca Pantea Stoian, Arrigo Francesco Giuseppe Cicero, Federica Fogacci, Dragana Nikolic, Alexandros Sachinidis, Ali A. Rizvi, Andrej Janez, Manfredi Rizzo
siRNAs are small dsRNAs (19–25 bp) that do not code to translate any molecule; they are significant mediators of the RNAi process, representing a novel therapeutic platform to exploit the natural mechanism of RNAi to inhibit protein synthesis. They are exogenously transfected into the cell and further incorporated into the RNAi machinery. Long dsRNAs, transfected in low concentrations to avoid immune response through the activation of the interferon pathway, are cleaved by Dicer, which is a dsRNA-specific ribonuclease, into 21–25 nucleotide-long ds siRNAs with two nucleotides in their 3ʹ overhang and 5ʹ phosphate groups. siRNAs are further recognized by the Argonaute 2 (AGO2) (a protein with a key role in RNA silencing) and RNA-induced silencing complex (RISC) (a multiribonucleoprotein complex) and unwind into their single-strand components [21–23]. The sense strand is degraded, and its complement-antisense strand binds via nucleotide complementarity targeting mRNA sequence. This is cleaved by AGO2 and degraded by exonucleases [24,25]. The result of such an association is solely dependent on the complementarity between siRNA and the target gene [26]. Although siRNAs have a specific target gene, they can also knock down unintended genes in two ways: (1) either deficient complementarity to non-targeted mRNAs or (2) by entering the endogenous miRNA machinery [26].
Optimization of siRNA delivery to target sites: issues and future directions
Published in Expert Opinion on Drug Delivery, 2018
Ikramy A. Khalil, Yuma Yamada, Hideyoshi Harashima
Bioconjugates are siRNA molecules that are covalently bound to different functional devices such as peptides, sugars, antibodies, lipids, or aptamers (Figure 1(a)). These functional devices are usually added to the 3ʹ or 5ʹ ends of the sense strand so as to not affect their ability to bind to target mRNA. The siRNA conjugates are ~10 nm in size, which allows them to be rapidly distributed to different organs, even in the absence of a discontinuous endothelium. However, this also means that they are highly susceptible to renal clearance [53]. The main purpose of siRNA bioconjugation varies but it is mostly performed for increasing stability or tissue targeting. Cholesterol and fatty acids are conjugated to siRNA to increase its stability against nucleases. These conjugates are taken up by hepatocytes through low-density lipoprotein (LDL) receptors. siRNA-cholesterol conjugates were used to silence apolipoprotein B (ApoB) in the liver for the treatment of hypercholesterolemia [54,55]. The stability of siRNA in the circulation is also improved by conjugation with different polyethylene glycol (PEG) derivatives. siRNA is also conjugated to cationic cell-penetrating peptides (CPPs) for protection and enhancing cellular uptake [56]. However, these cationic conjugates are generally nonspecific and readily interact with serum-negative components, which limits their efficiency after systemic administration.