Can RNAi be used as a weapon against COVID-19/SARSCoV-2? (original) (raw)
Related papers
2022
RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral genome. We screened lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 genome and identified leads targeting outside of the spike-encoding region capable of achieving ≥3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. A two-siRNA combination delivered intranasally protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach to limit SARS-CoV-2 infection that may help combat emergent variants, complement existing interventions, or protect populations where vaccines are less effective. Most importantly, this stra...
RNAi suppressor: The hidden weapon of SARS-CoV
Journal of Biosciences
The two biological evidences to endorse the antiviral activity of RNA interference (RNAi) are biogenesis of viral-siRNA (v-siRNA) by the host and encoding of RNAi-suppressor protein by viral genome. It has been recently established that mammals and mammalian cell lines mount antiviral RNAi to defend themselves against the invading viruses. The large part of viral pathogenicity is also due to the RNAi suppressor proteins. In this context it is only natural to ask what kinds of RNAi suppressors are encoded by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the central character of the present pandemic. The following mini review addresses this question.
2020
RNAi is a natural cellular progression of gene silencing that represents one of the most promising and rapidly advancing frontiers in microbiology and drug invention today. Its discovery has been considered as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006Nobel Prize for Physiology or Medicine. RNAi is an adaptive cellular defense mechanism, is a worldwide denominator for the Post-transcriptional Gene Silencing (PTGS) phenomenon observed in a variety of living species including plants and animals. It is a dominant reverse genetic procedure that has been extensively employed to silence gene expression in human cells. RNAibased gene therapies, especially in viral diseases have become more and more interesting and promising. Recently, siRNA can be used to defend host from viral infection, inhibit the expression of viral antigen and accessory genes, control the transcription and replication of viral genome, obstruct ...
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
Suppression of Human Coronavirus 229E Infection in Lung Fibroblast Cells via RNA Interference
Frontiers in Nanotechnology
Despite extensive efforts to repurpose approved drugs, discover new small molecules, and develop vaccines, COVID-19 pandemic is still claiming victims around the world. The current arsenal of antiviral compounds did not perform well in the past viral infections (e.g., SARS), which casts a shadow of doubt for use against the new SARS-CoV-2. Vaccines should offer the ultimate protection; however, there is limited information about the longevity of the generated immunity and the protection against possible mutations. This study uses Human Coronavirus 229E as a model coronavirus to test the hypothesis that effective delivery of virus-specific siRNAs to infected cells will result in lower viral load and reduced cell death. Two different categories of nucleic acid delivery systems, Peptide/Lipid-Associated Nucleic Acids (PLANAs) and lipophilic polymers, were investigated for their toxicity in human lung fibroblast cells and their ability to deliver specific siRNAs targeting Spike and Enve...
Molecular targeting of vulnerable RNA sequences in SARS CoV-2: identifying clinical feasibility
Gene Therapy
Covid-19 (SARS CoV-2) has become a deadly, worldwide pandemic. Although most who are infected survive, complications from the virus can be pronounced and long-lasting. To date, of all the respiratory viruses including influenza and coronaviruses, only influenza has had a drug (i.e., Tamiflu) specifically targeted to treat and prevent infection. As a result, additional agents that specifically target viral production and are clinically feasible are needed to alleviate respiratory viral infections. The idea of using a miRNA/siRNA molecular approach for treating various diseases was postulated over a decade ago; however, only within the past few years has it become feasible. One technological advancement has been the molecular linkage of lipophilic moieties to mi/siRNAs in order to bypass the need for enveloping these inhibitory RNAs in lipid-based transfection reagents, which could irritate the airway if inhaled. Here we show that siRNAs and miRNAs inhibit SARS CoV-2 spike protein production in a dose-dependent manner in both HEK293 cells and a primary human airway tracheal cell line. We also show that this inhibition is equally robust using a clinically relevant siRNA that does not need to be prepped with a transfection reagent.
Protection against lethal influenza virus challenge by RNA interference in vivo
Proceedings of the National Academy of Sciences of the United States of America, 2004
Influenza virus infection is responsible for hundreds of thousands of deaths annually. Current vaccination strategies and antiviral drugs provide limited protection; therefore, new strategies are needed. RNA interference is an effective means of suppressing virus replication in vitro. Here we demonstrate that treatment with small interfering RNAs (siRNAs) specific for highly conserved regions of the nucleoprotein or acidic polymerase inhibits influenza A virus replication in vivo. Delivery of these siRNAs significantly reduced lung virus titers in infected mice and protected animals from lethal challenge. This protection was specific and not mediated by an antiviral IFN response. Moreover, influenza-specific siRNA treatment was broadly effective and protected animals against lethal challenge with highly pathogenic avian influenza A viruses of the H5 and H7 subtypes. These results indicate that RNA interference is promising for control of influenza virus infection, as well as other viral infections.
Inhibition of influenza virus production in virus-infected mice by RNA interference
Proceedings of The National Academy of Sciences, 2004
Influenza A virus infection is a major source of morbidity and mortality worldwide. Because the effectiveness of existing vaccines and antiviral drugs is limited, development of new treatment modalities is needed. Here, we show that short interfering RNAs (siRNAs) specific for conserved regions of influenza virus genes can prevent and treat influenza virus infection in mice. Virus production in lungs of infected mice is reduced by siRNAs given either before or after initiating virus infection, by using slow i.v. administration of small volumes containing siRNAs in complexes with a polycation carrier. Similar effects also are observed when mice are given DNA vectors i.v. or intranasally, from which siRNA precursors can be transcribed. Development of delivery systems that may be compatible with human use demonstrates the potential utility of siRNAs for prophylaxis and therapy of influenza virus infections in humans.