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.
Highlights
SARS-CoV-2’s Life Cycle and “Druggable” TargetsSARS-CoV-2 belongs to the betacoronavirus genus and is an enveloped ssRNA (+) virus with a genome length of about 30,000 nucleotides (RefSeq NC_045512) (Wu et al, 2020)
An RNA-dependent RNA polymerase (RdRP) complex consisting of nsp12 in pp1ab and nsps7 and 8 in pp1a is required for viral transcription and replication (Hillen et al, 2020)
We focused on the RNA-targeting approach, an emerging antiviral pharmacological modality that is complementary to traditional protein-targeting methods
Summary
SARS-CoV-2 belongs to the betacoronavirus genus and is an enveloped ssRNA (+) virus with a genome length of about 30,000 nucleotides (RefSeq NC_045512) (Wu et al, 2020). Among all SARS-CoV-2 RNA structures identified, the 5’ and 3’ UTRs and a region named programmed –1 frameshift (PFS) element (13,459–13,546) in the ORF1a/ab have been intensively studied for their structures, functions, and druggability. It was demonstrated by psoralen crosslinking that the 3’-end of the genome in the Stem 3 region can bind to the viral 5’ UTR and cyclize the SARS-CoV-2 genome (Ziv et al, 2020). Anti-SARS-CoV-2 ASOs By using 3D antisense modeling, a PMO named PRF3p was optimized to target the Stem 3 region in the PFS element (Li et al, 2021b) (Figure 5). A PMO named SBD1 was designed to target the conserved TRS-L region in the SARS-CoV 5’ UTR (Figure 5), and thereby inhibited the “discontinuous” transcription (Li et al, 2021b). 29–44 6,451–6,471 9,458–9,478 29,497–29,517 59–72 & 79–85b 13,503–13,506 and 13,534–13,551b 29,734–29,749 29,739–29,754 13,526–13,540 13,516-13,529 13,511–13,526 13,463–13,479
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