Inhibition of SARS-CoV-2 by Targeting Conserved Viral RNA Structures and Sequences

Abstract

The ongoing COVID-19/Severe Acute Respiratory Syndrome CoV-2 (SARS-CoV-2) pandemic has become a significant threat to public health and has hugely impacted societies globally. Targeting conserved SARS-CoV-2 RNA structures and sequences essential for viral genome translation is a novel approach to inhibit viral infection and progression. This new pharmacological modality compasses two classes of RNA-targeting molecules: 1) synthetic small molecules that recognize secondary or tertiary RNA structures and 2) antisense oligonucleotides (ASOs) that recognize the RNA primary sequence. These molecules can also serve as a “bait” fragment in RNA degrading chimeras to eliminate the viral RNA genome. This new type of chimeric RNA degrader is recently named ribonuclease targeting chimera or RIBOTAC. This review paper summarizes the sequence conservation in SARS-CoV-2 and the current development of RNA-targeting molecules to combat this virus. These RNA-binding molecules will also serve as an emerging class of antiviral drug candidates that might pivot to address future viral outbreaks.

Statistical analysis supports UTR (untranslated region) deletion theory in SARS-CoV-2

“…It was proposed that the UTR can form multiple stem-loop secondary structures which greatly enhanced its conservation in structure. A detailed description of its secondary structure is shown in a recent review done by Shalakha Hegde et al [ 38 ]. For SARS-CoV-2, in the 5’ UTR (1–265), there are five stem-loops identified, SL1–5.…”

“…This hypothesis is physically supported by its RNA structure. Its RNA forms a variety of stem-loop structures, and the highly complemented area might perform as a bottleneck in the degradation by RNA exonucleases [ 38 , 45 , 46 ]. This hypothesis can also explain why the gene length distribution of the SARS-CoV-2 population does not conform to the orthographic distribution or random distribution but has significant hotspots at some specific length loci.…”

Translational Control of COVID-19 and Its Therapeutic Implication

“…Targeting conserved RNA structures and sequences of SARS-CoV-2 is an alternative approach to inhibiting viral infection and progression ( 209 , 210 ). The most well-known examples are antisense oligonucleotides (ASOs), which contain modifications at their positions, such as 2-O-methyl (2-OME), 2-O-methoxy (2-MOE), locked nucleic acid (LNA), morpholino, or other nucleotide modifications, which may increase RNA base pairing, metabolic stability, and/or delivery ( 209 , 211 , 212 ). Circular RNAs (circRNAs) can also be engineered as antisense RNAs to disrupt SARS-CoV-2 genome expression and viral proliferation ( 213 ).…”

Safety and biodistribution of Nanoligomers™ targeting SARS-CoV-2 genome for treatment of COVID-19

“…Other antisense oligonucleotides designed to directly target the SARS-CoV-2 genome bind untranslated regions or transcriptional regulatory sequences and are early in development. 25 Direct-acting antivirals (DAAs) such as these are beneficial as treatment options as they do not rely on the activity of the host immune system and can act immediately upon any present viral particles rather than depending on administration at optimal infection progression. 26 The antiviral compound presented here, called SBCoV202, was developed by Sachi Bioworks, Inc, and relies on antisense technology.…”