Efficient Inhibition of SARS‐CoV‐2 Using Chimeric Antisense Oligonucleotides through RNase L Activation**

Abstract

There is an urgent need to develop antiviral drugs and alleviate the current COVID‐19 pandemic. Herein we report the design and construction of chimeric oligonucleotides comprising a 2′‐OMe‐modified antisense oligonucleotide and a 5′‐phosphorylated 2′‐5′ poly(A)4 (4A2‐5) to degrade envelope and spike RNAs of SARS‐CoV‐2. The oligonucleotide was used for searching and recognizing target viral RNA sequence, and the conjugated 4A2‐5 was used for guided RNase L activation to sequence‐specifically degrade viral RNAs. Since RNase L can potently cleave single‐stranded RNA during innate antiviral response, degradation efficiencies with these chimeras were twice as much as those with only antisense oligonucleotides for both SARS‐CoV‐2 RNA targets. In pseudovirus infection models, chimera‐S4 achieved potent and broad‐spectrum inhibition of SARS‐CoV‐2 and its N501Y and/or ΔH69/ΔV70 mutants, indicating a promising antiviral agent based on the nucleic acid‐hydrolysis targeting chimera (NATAC) strategy.

Evaluation of the role of HIS-1 and HSP-70 genes in pathology and response to the drugs by antisense oligonucleotides in Leishmania major

“…In this study, ASO in different concentrations were used to decrease the expression of HSP-70 and HIS-1 genes related to L. major. The use of ASO in recent years has attracted the attention of many researchers in the eld of pharmacy, especially for the treatment of infectious diseases, and has been used as an alternative treatment for chemical drugs and even as a vaccine [21][22][23]. Crater et al, (2015) used ASO on Toxoplasma gondii gene expression and stated that ASO could be used alongside other common methods to reduce the gene expression of the exact genes [24].…”

“…Vaccination is an alternative method for the control of infectious diseases. Antisense oligonucleotides (ASOs) are the chemically manufactured oligonucleotides with commonly [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] nucleotides that are planned to bind to RNA to control RNA purpose by numerous diverse mechanisms [10][11][12].…”

Efficient Targeted Delivery of Bifunctional Circular Aptamer ASO Chimera to Suppress the SARS-CoV-2 Proliferation and Inflammation

“…Unfortunately, unnatural nucleotides may lead to toxicity or immunogenicity 18 , affecting the structure of the original aptamers 19 . Several potential oligonucleotidebased therapies for SARS-CoV-2 are currently investigated, including siRNA-based therapies that targeted ORF1 20 , locked nucleic acid antisense oligonucleotides targeting SL1 21,22 , ASO with the phosphorodiamidate morpholino (PMO) modi cation that targeted PRF and TRS 23 , and ASO-speci c ligand 5' phosphorylated 2'-5' polyA chimeras targeting envelope or spike RNA 24 . Besides, aptamers targeting SARS-CoV-2 represent a promising alternative tool against COVID-19.…”