<i>In Silico</i>Design of siRNAs Targeting Existing and Future Respiratory Viruses with VirusSi

Zhang, Dingyao; Lü, Jun

doi:10.1101/2020.08.13.250076

Cited by 7 publications

(7 citation statements)

References 33 publications

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“…During in silico prediction, many siRNAs were found to fulfill the less favorable criteria targeting a region in the ORF1ab gene of MERS-CoV. By using strong selection criteria and a stringent strategy, we have selected and filtered out a total of twenty-one functional, off-target siRNAs that were shortlisted from four hundred and sixty-two siRNAs as per the guidelines and basic rules of filtration [ 18 , 35 , 36 , 39 , 40 ]. The designed siRNAs’ length, nucleotide content and specificity and absence of off-target effects and secondary structures in the target site were taken into consideration by the used software during the design and filtering of the siRNAs as this would influence the efficiency, precision, and functionality of siRNAs, hence leading to a better silencing outcome [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

“…Other structure-based approaches use the ability of small molecules to target specific RNA structures or recognize and bind to RNA targets based on their secondary or tertiary structures [ 24 , 33 , 34 ]. Recently, in silico designing of siRNAs against respiratory viruses has been reported [ 18 , 35 , 36 ] including evaluation of siRNAs against MERS-CoV. We have previously performed in silico prediction alongside a pilot study for investigating the antiviral activity for 10 of the described siRNAs in a different cell culture system [ 30 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Inhibitory Analysis of Rationally Designed siRNAs against MERS-CoV Replication in Huh7 Cells

et al. 2021

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MERS-CoV was identified for the first time in Jeddah, Saudi Arabia in 2012 in a hospitalized patient. This virus subsequently spread to 27 countries with a total of 939 deaths and 2586 confirmed cases and now has become a serious concern globally. Camels are well known for the transmission of the virus to the human population. In this report, we have discussed the prediction, designing, and evaluation of potential siRNA targeting the ORF1ab gene for the inhibition of MERS-CoV replication. The online software, siDirect 2.0 was used to predict and design the siRNAs, their secondary structure and their target accessibility. ORF1ab gene folding was performed by RNAxs and RNAfold software. A total of twenty-one siRNAs were selected from 462 siRNAs according to their scoring and specificity. siRNAs were evaluated in vitro for their cytotoxicity and antiviral efficacy in Huh7 cell line. No significant cytotoxicity was observed for all siRNAs in Huh7 cells. The in vitro study showed the inhibition of viral replication by three siRNAs. The data generated in this study provide preliminary and encouraging information to evaluate the siRNAs separately as well as in combination against MERS-CoV replication in other cell lines. The prediction of siRNAs using online software resulted in the filtration and selection of potential siRNAs with high accuracy and strength. This computational approach resulted in three effective siRNAs that can be taken further to in vivo animal studies and can be used to develop safe and effective antiviral therapies for other prevalent disease-causing viruses.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vitro Inhibitory Analysis of Rationally Designed siRNAs against MERS-CoV Replication in Huh7 Cells

et al. 2021

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“…Beyond nucleic acid diagnostics, finding maximally active and taxon-specific sequences in viral genomes has other uses that fit into ADAPT’s framework. For example, sequence diversity impacts the efficacy of sequence-based siRNAs 55 and antibody therapeutics 56 . CRISPR-based antiviral development also requires consideration of sequence diversity, guide activity, and specificity 57 .…”

Section: Discussionmentioning

confidence: 99%

“…Beyond viral diagnostics, our approach can benefit other efforts that require designing maximally active sequences from viral genome data. For example, genomic variation impacts the efficacy of sequence-based siRNA 64 and antibody 65 therapeutics. CRISPR-based antiviral development also requires deep consideration of sequence diversity, guide activity, and taxon-specificity 66 .…”

Section: Discussionmentioning

confidence: 99%

Designing viral diagnostics with model-based optimization

Metsky

Welch

Pillai

et al. 2020

Preprint

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Harnessing genomic data and predictive models will provide activity-informed diagnostic assays for thousands of viruses and offer rapid design for novel ones. Here we develop and extensively validate new algorithms that design nucleic acid assays having maximal predicted detection activity over a virus’s full genomic diversity with stringent specificity. Focusing on CRISPR-Cas13a detection, we test a library of ~ 19,000 guide-target pairs and construct a convolutional neural network that predicts Cas13a detection activity better than other techniques. We link our methods by building ADAPT, an end-to-end system that automatically leverages the latest viral genome data. We designed optimal species-specific assays for the 1,933 vertebrate-infecting viral species within 2 hours for most species and 24 hours for all but 3. ADAPT’s designs are sensitive and specific down to the lineage-level for the range of taxa we tested, including ones that pose challenges involving genomic diversity and specificity. They also exhibit significantly higher fluorescence and lower limits of detection, across a virus’s full spectrum of genomic diversity, than designs from standard techniques. ADAPT is available in an accessible software package and can be applied to other detection technologies to enhance critically-needed viral diagnostic and surveillance efforts.

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“…This revealed that four siRNAs (3329i, 1878i, 1104i, and 2351i) were able to decrease the expression of the S gene, and four other siRNAs (418i, 881i, 214i, and 1068i) could separately reduce the expression of the N gene, while the remaining three siRNAs (607i, 344i, and 79i) could decrease the M gene expression [ 104 ]. Several researchers have also predicted functional and potential siRNAs as therapeutics using in silico analysis [ 105 , 106 ] ( Table 1 ).…”

Section: Sirna Therapy—a Potential and Promising Antiviral Therapeuticmentioning

confidence: 99%

Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract

Zhang

Almazi

Ong

et al. 2022

IJMS

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Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases.

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In SilicoDesign of siRNAs Targeting Existing and Future Respiratory Viruses with VirusSi

Cited by 7 publications

References 33 publications

In Vitro Inhibitory Analysis of Rationally Designed siRNAs against MERS-CoV Replication in Huh7 Cells

In Vitro Inhibitory Analysis of Rationally Designed siRNAs against MERS-CoV Replication in Huh7 Cells

Designing viral diagnostics with model-based optimization

Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract

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