mRNA– i TECHNOLOGY- A NOVEL AND UNIQUE APPROACH AND STRATEGY FOR PROPHYLAXIS AND TREATMENT OF COVID 19 (original) (raw)

Antiviral RNAi: How to Silence Viruses

Methods and Principles in Medicinal Chemistry, 2011

RNAi is a cellular mechanism that can be induced by siRNAs to mediate the sequence-specific gene knockdown by cleavage or translational repression of the targeted mRNA. The initial phenomenon that led to the discovery of RNAi was made by Jorgensen and colleagues in petunia flowers that turned partially or completely white after the introduction of a pigment-producing gene that was supposed to deepen the purple color [1]. Around the same time, van der Krol et al. reported similar observations in petunias [2]. Soon thereafter, similar phenomena were described in the fungi Neurospora crassa by Romano and Macino, where this posttranscriptional gene silencing (PTGS) is also known as quelling [3]. Fire et al. described the RNAi phenomenon in mechanistic terms in the nematode Caenorhabditis elegans. Efficient sequence-specific gene silencing was observed upon introduction of double-stranded RNA (dsRNA) [4]. Injection of dsRNA corresponding to different genes resulted in a specific null mutant phenotype in Drosophila [5, 6]. Subsequently, RNAi was also described in Trypanosoma brucei [7], zebrafish [8], and mice [9]. Introduction of base paired 21-nucleotide dsRNA into mammalian cell lines also triggered sequencespecific gene silencing [10]. This discovery triggered the development of RNAi-based therapies against a wide variety of diseases, including cancer, neurological, autoimmune, and infectious diseases [11-17]. 13.2 Therapeutic Application of the RNAi Mechanism Antiviral Drug Strategies, First Edition. Edited by Erik De Clercq.

RNA interference for antiviral therapy

The Journal of Gene Medicine, 2006

Silencing gene expression through a process known as RNA interference (RNAi) has been known in the plant world for many years. In recent years, knowledge of the prevalence of RNAi and the mechanism of gene silencing through RNAi has started to unfold. It is now believed that RNAi serves in part as an innate response against invading viral pathogens and, indeed, counter silencing mechanisms aimed at neutralizing RNAi have been found in various viral pathogens. During the past few years, it has been demonstrated that RNAi, induced by specifically designed double-stranded RNA (dsRNA) molecules, can silence gene expression of human viral pathogens both in acute and chronic viral infections. Furthermore, it is now apparent that in in vitro and in some in vivo models, the prospects for this technology in developing therapeutic applications are robust. However, many key questions and obstacles in the translation of RNAi into a potential therapeutic platform still remain, including the specificity and longevity of the silencing effect, and, most importantly, the delivery of the dsRNA that induces the system. It is expected that for the specific examples in which the delivery issue could be circumvented or resolved, RNAi may hold promise for the development of gene-specific therapeutics. Copyright  2006 John Wiley & Sons, Ltd. Keywords acute viral infection; chronic viral infection RNA interference; antiviral therapy; gene therapy Inhibition of viral transcription by siRNAs After entering the target cells, the virus has to transcribe its genome. In order to do so, the viruses use the host cell machinery, and many viruses also use their own

siRNA could be a potential therapy for COVID-19

EXCLI Journal, 2020

Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded non-coding RNA molecules, which is 20-25 base pairs in length. siRNAs can regulate the expression of genes, by a phenomenon known as RNA interference (RNAi). Based on the phenomenon, the siRNA based therapeutics have been developed and implemented for anticancer, antiviral, and genetic diseases (Liu et al., 2020). In December 2019, WHO reported the outbreak of a novel coronavirus, designated as SARS-CoV-2 or severe acute respiratory syndrome-related coronavirus. This virus has currently spread across 212 countries which resulted in 2,416,135 active cases of infection, and approximately 165,939 mortalities, as per WHO (2020). There are many drugs currently being tested which include antiviral (remdesivir, favipiravir, lopinavir, ritonavir, and arbidol), antimalarial (hydroxychloroquine), and anticancer (interferon-alpha 2b) agents. These drug candidates are undergoing clinical trials, and their efficacy against SARS-CoV-2 has yet to be proven. Under such a situation, siRNA based treatment can provide an effective solution in combating COVID-19 (Liu et al., 2020). Some earlier studies revealed that siRNA candidates were effectively used against the outbreak of SARS and Middle-East Respiratory Syndrome (MERS), recapitulated in Table 1. The siRNAs identified successfully targeted the sequences which coded for the viral RNAdependent RNA polymerase, helicase, proteolytic enzymes, and the nucleoprotein N of earlier SARS virus leading to a 50, 70, 90, and 95 % decrease in viral load, respectively. The viral genome of SARS-CoV-2 is 29 kbp in size and one of the largest genomes among the RNA virus. This genome consists of fourteen open reading frames (ORFs) which coded for twentyseven structural and nonstructural proteins (Wu et al., 2020a). At the 5' end, there are the two largest ORFs, namely ORF1a and ORF1b which are translated into a single large poly-protein by the ribosome through a frame-shift event. The ORF1a comprises of two viral cysteine pro

Can RNAi be used as a weapon against COVID-19/SARSCoV-2?

2020

Can RNA interference be used as a diagnostic and therapeutic for COVID-19? Can host or viral encoded miRNA or siRNA be used as a vaccine against SARS-CoV-2? RNAi has been used as a platform to make attenuated viral vaccines where the viral genome is engineered and modified to contain miRNA or siRNA binding sites [50]. One of these examples was the creation of self-attenuating Influenza A virus strain that expressed an siRNA from the NS segment (for wild type nonstructural protein NS1) that targets the ORF of the nucleoprotein [NP] segment just at a single site [51]. Intranasal administration of five chemically modified miRNA mimics corresponding to highly expressed miRNAs in respiratory epithelial cells synergistically suppressed H1N1 replication in mice. MicroRNA 122 is another most common example in RNAi literature, antimiR against mir-122 is effective to lower the hepatitis C virus and miR-122 inhibition by anti-miR122 also reduces serum cholesterol levels [40,52]. RNAi patents a...

RNAi therapeutics: an antiviral strategy for human infections

Current Opinion in Pharmacology, 2020

Gene silencing induced by RNAi represents a promising antiviral development strategy. This review will summarise the current state of RNAi therapeutics for treating acute and chronic human virus infections. The gene silencing pathways exploited by RNAi therapeutics will be described and include both classic RNAi, inducing cytoplasmic mRNA degradation post-transcription and novel RNAi, mediating epigenetic modifications at the transcription level in the nucleus. Finally, the challenge of delivering gene modifications via RNAi will be discussed, along with the unique characteristics of respiratory versus systemic administration routes to highlight recent advances and future potential of RNAi antiviral treatment strategies.