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Deciphering inhibitory mechanism of coronavirus replication through host miRNAs-RNA-dependent RNA polymerase
Olanrewaju B Morenikeji1, Muyiwa S Adegbaju2, Olayinka S Okoh3
1Division of Biological and Health Sciences, University of Pittsburgh at Bradford, Bradford, PA, United States.
Abstract:
Despite what we know so far, Covid-19, caused by SARS-CoV-2 virus, remains a pandemic that still require urgent healthcare intervention. The frequent mutations of the SARS-CoV-2 virus has rendered disease control with vaccines and antiviral drugs quite challenging, with newer variants surfacing constantly. There is therefore the need for newer, effective and efficacious drugs against coronaviruses. Considering the central role of RNA dependent, RNA polymerase (RdRp) as an enzyme necessary for the virus life cycle and its conservation among coronaviruses, we investigated potential host miRNAs that can be employed as broad-range antiviral drugs averse to coronaviruses, with particular emphasis on BCoV, MERS-CoV, SARS-CoV and SARS-CoV-2. miRNAs are small molecules capable of binding mRNA and regulate expression at transcriptional or translational levels. Our hypothesis is that host miRNAs have the potential of blocking coronavirus replication through miRNA-RdRp mRNA interaction. To investigate this, we retrieved the open reading frame (ORF1ab) nucleotide sequences and used them to interrogate miRNA databases for miRNAs that can bind them. We employed various bioinformatics tools to predict and identify the most effective host miRNAs. In all, we found 27 miRNAs that target RdRp mRNA sequence of multiple coronaviruses, of which three - hsa-miR-1283, hsa-miR-579-3p, and hsa-miR-664b-3p target BCoV, SARS-CoV and SARS-CoV-2. Additionally, hsa-miR-374a-5p has three bovine miRNA homologs viz bta-miR-374a, bta-miR-374b, and bta-miR-374c. Inhibiting the expression of RdRp enzyme via non-coding RNA is novel and of great therapeutic importance in the control of coronavirus replication, and could serve as a broad-spectrum antiviral, with hsa-miR-1283, hsa-miR-579-3p, and hsa-miR-664b-3p as highly promising.
Insights
Novel host microRNAs (miRNAs) show promise in combating coronaviruses by targeting the essential RNA-dependent RNA polymerase (RdRp). These findings could lead to broad-spectrum antiviral therapies against SARS-CoV-2 and other coronaviruses.
Area of Science:
- Virology and Molecular Biology
- Bioinformatics and Computational Biology
- Antimicrobial Drug Discovery
Background:
- The ongoing COVID-19 pandemic, caused by SARS-CoV-2, necessitates new therapeutic strategies due to frequent viral mutations challenging existing vaccines and antivirals.
- The RNA-dependent RNA polymerase (RdRp) is a crucial enzyme for coronavirus replication and is conserved across different coronavirus species, making it a potential therapeutic target.
- Host microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and present an opportunity for novel antiviral development.
Purpose of the Study:
- To identify host miRNAs capable of targeting the RdRp mRNA sequence of various coronaviruses, including Bovine Coronavirus (BCoV), MERS-CoV, SARS-CoV, and SARS-CoV-2.
- To investigate the potential of these host miRNAs as broad-spectrum antiviral agents against coronaviruses.
- To explore the therapeutic implications of inhibiting viral RdRp expression using non-coding RNAs.
Main Methods:
- Retrieved open reading frame (ORF1ab) nucleotide sequences for multiple coronaviruses.
- Utilized bioinformatics tools to screen miRNA databases for potential binding targets within the RdRp mRNA sequence.
- Predicted and identified specific host miRNAs demonstrating high binding affinity and efficacy against RdRp.
Main Results:
- Identified 27 host miRNAs capable of targeting the RdRp mRNA sequence across various coronaviruses.
- Discovered three specific human miRNAs (hsa-miR-1283, hsa-miR-579-3p, and hsa-miR-664b-3p) that effectively target RdRp in BCoV, SARS-CoV, and SARS-CoV-2.
- Found that hsa-miR-374a-5p has homologous counterparts in bovine miRNAs (bta-miR-374a, bta-miR-374b, bta-miR-374c).
Conclusions:
- Host miRNAs, particularly hsa-miR-1283, hsa-miR-579-3p, and hsa-miR-664b-3p, show significant potential as broad-spectrum antiviral agents against coronaviruses.
- Inhibiting coronavirus replication by targeting the essential RdRp enzyme via non-coding RNA represents a novel and therapeutically important strategy.
- These identified miRNAs offer promising candidates for the development of new antiviral therapies to combat current and future coronavirus outbreaks.
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