Potential Use of Noncoding RNAs and Innovative Therapeutic Strategies to Target the 5’UTR of SARS-CoV-2

Abstract

After the increasing number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections all over the world, researchers and clinicians are struggling to find a vaccine or innovative therapeutic strategies to treat this viral infection. The severe acute respiratory syndrome coronavirus infection that occurred in 2002, Middle East respiratory syndrome (MERS) and other more common infectious diseases such as hepatitis C virus, led to the discovery of many RNA-based drugs. Among them, siRNAs and antisense locked nucleic acids have been demonstrated to have effective antiviral effects both in animal models and humans. Owing to the high genomic homology of SARS-CoV-2 and severe acute respiratory syndrome coronavirus (80–82%) the use of these molecules could be employed successfully also to target this emerging coronavirus. Trying to translate this approach to treat COVID-19, we analyzed the common structural features of viral 5’UTR regions that can be targeted by noncoding RNAs and we also identified miRNAs binding sites suitable for designing RNA-based drugs to be employed successfully against SARS-CoV-2.

The epigenetic implication in coronavirus infection and therapy

“…Epigenomic studies might open new avenues for developing antiviral drugs by evaluating specific epigenetic modulators as targets and exploring new chromatin-based therapies for different virus families, including Coronaviruses, which could reveal fundamental new landscapes of virus–host interaction and their role in disease severity [ 85 ]. Previous works focused on specific epigenetic mechanisms [ 83 , 101 ]. This article summarizes the comprehensive knowledge about epigenetic aspects associated with SARS-CoV-2 infection and suggests potential epigenetically based therapies.…”

“…RNA-based drugs are other epigenetic tools that should be investigated for treating viral infections [99,100]. For instance, among all the SARS-CoV genome that have been under study so far, Baldassarre and coworkers suggested that the 5′URT region and specific portion of it, which are essential for viral RNA replication and transcription, could be considered relevant to design novel therapeutic molecules to treat the infection [101]. Novel strategies employing small interfering RNAs (siRNAs), microRNAs (miRNAs), and locked nucleic acid antisense oligonucleotides (LNA) or GapmeRs, targeting, for instance, the 5′URT or regions of the Spike molecule, represent potential therapeutic tools for both prophylaxis and therapy of COVID-19 [101][102][103].…”

“…For instance, among all the SARS-CoV genome that have been under study so far, Baldassarre and coworkers suggested that the 5′URT region and specific portion of it, which are essential for viral RNA replication and transcription, could be considered relevant to design novel therapeutic molecules to treat the infection [ 101 ]. Novel strategies employing small interfering RNAs (siRNAs), microRNAs (miRNAs), and locked nucleic acid antisense oligonucleotides (LNA) or GapmeRs, targeting, for instance, the 5′URT or regions of the Spike molecule, represent potential therapeutic tools for both prophylaxis and therapy of COVID-19 [ 101 – 103 ]. Indeed, the design of antisense oligonucleotides, such as Miravirsen, under investigation for HCV treatment, could be used to inhibit viral replication by scavenging miRNAs that are involved in the process [ 104 , 105 ].…”

Systematic analysis of RNAi-accessible SARS-CoV-2 replication steps identifies ORF1 as promising target

“…While some progress has been made by repurposing the RNA polymerase inhibitor Remdesivir (5) or by ameliorating SARS-CoV-2 induced lung injury using Dexamethason (6), lethality of COVID-19 remains high (7). A promising alternative approach could be to deliver small interfering (si)RNAs (8)(9)(10)(11) to the respiratory tract by inhalation (12) and induce degradation of viral RNAs by the RNA-interference (RNAi) machinery. Studies performed with Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1) or Middle East Respiratory Syndrome Coronavirus (MERS-CoV), showed that siRNAs can silence viral RNA and relieve symptoms caused by related coronaviruses (13)(14)(15)(16)(17).…”

“…Studies performed with Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1) or Middle East Respiratory Syndrome Coronavirus (MERS-CoV), showed that siRNAs can silence viral RNA and relieve symptoms caused by related coronaviruses (13)(14)(15)(16)(17). However, while several publications have proposed siRNAs as potential therapeutic also for COVID-19 (8)(9)(10)(11), until today there is no proof that SARS-CoV-2 can be inhibited by siRNAs, not to mention a detailed systematic analysis, which replication steps are accessible for RNAi. SARS-CoV-2, as other coronaviruses, has a positive sense, single-stranded RNA genome with a length of approximately 30,000 nucleotides.…”