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Published on: May 5, 2014
Evitar: designing anti-viral RNA therapies against future RNA viruses
Dingyao Zhang1,2, Jingru Tian1,2, Yadong Wang1,2,3
1Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
Motivation:
The coronavirus disease 2019 (COVID-19) pandemic has highlighted the threat of emerging respiratory viruses and has exposed the lack of availability of off-the-shelf therapeutics against new RNA viruses. Previous research has established the potential that siRNAs and RNA-targeting CRISPR have in combating known RNA viruses. However, the feasibility and tools for designing anti-viral RNA therapeutics against future RNA viruses have not yet been established.
Results:
We develop the Emerging-Virus-Targeting RNA (Evitar) pipeline for designing anti-viral siRNAs and CRISPR Cas13a guide RNA (gRNA) sequences. Within Evitar, we develop Greedy Algorithm with Redundancy and Similarity-weighted Greedy Algorithm with Redundancy to enhance the performance. Time simulations using known coronavirus genomes deposited as early as 10 years prior to the COVID-19 outbreak show that at least three SARS-CoV-2-targeting siRNAs are among the top 30 pre-designed siRNAs. In addition, among the top 19 pre-designed gRNAs, there are three SARS-CoV-2-targeting Cas13a gRNAs that could be predicted using information from 2011. Before-the-outbreak design is also possible against the MERS-CoV virus and the 2009-H1N1 swine flu virus. Designed siRNAs are further shown to suppress SARS-CoV-2 viral sequences using in vitro reporter assays. Our results support the utility of Evitar to pre-design anti-viral siRNAs/gRNAs against future viruses. Therefore, we propose the development of a collection consisting of roughly 30 pre-designed, safety-tested and off-the-shelf siRNA/CRISPR therapeutics that could accelerate responses to future RNA virus outbreaks.
Availability And Implementation:
Codes are available at GitHub (https://github.com/dingyaozhang/Evitar).
Supplementary Information:
Supplementary data are available at Bioinformatics online.
Insights
We developed Evitar, a pipeline for designing RNA therapeutics like siRNAs and CRISPR guide RNAs against emerging viruses. Evitar can predict effective therapeutics for future outbreaks, accelerating pandemic response.
Area of Science:
- Virology
- Bioinformatics
- RNA Therapeutics
Background:
- Emerging RNA viruses pose significant threats, as demonstrated by the COVID-19 pandemic.
- Current therapeutic options for novel RNA viruses are limited, highlighting the need for rapid development tools.
Purpose of the Study:
- To develop a computational pipeline (Evitar) for designing RNA-targeting therapeutics (siRNAs and CRISPR Cas13a gRNAs) against emerging RNA viruses.
- To enable pre-outbreak design of therapeutics for potential future viral threats.
Main Methods:
- Developed the Evitar pipeline incorporating Greedy Algorithm with Redundancy and Similarity-weighted Greedy Algorithm with Redundancy.
- Utilized historical coronavirus genomes for pre-outbreak siRNA and gRNA design simulations.
- Validated designed siRNAs through in vitro reporter assays against SARS-CoV-2 sequences.
Main Results:
- Evitar successfully identified potential SARS-CoV-2 targeting siRNAs and CRISPR Cas13a gRNAs using genomic data predating the COVID-19 outbreak.
- Pre-outbreak therapeutic designs were feasible for MERS-CoV and 2009-H1N1 swine flu viruses.
- In vitro assays confirmed the ability of designed siRNAs to suppress SARS-CoV-2 viral sequences.
Conclusions:
- The Evitar pipeline is effective for designing anti-viral siRNAs and gRNAs against future RNA viruses.
- Propose creating a collection of pre-designed, off-the-shelf siRNA/CRISPR therapeutics to expedite responses to future viral outbreaks.
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