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Antisense Oligonucleotides to Therapeutically Target SARS-CoV-2 Infection

Yuanyuan Qiao, Jesse W. Wotring, Charles J. Zhang, Xia Jiang, Lanbo Xiao, Andy Watt, Danielle Gattis, Eli Scandalis, Susan Freier, Yang Zheng, Carla D. Pretto, Stephanie J. Ellison, Eric E. Swayze, Shuling Guo, Jonathan Z. Sexton, Arul M. Chinnaiyan.


Although the COVID-19 pandemic began over three years ago, the virus responsible for the disease, SARS-CoV-2, continues to infect people across the globe. As such, there remains a critical need for development of novel therapeutics against SARS-CoV-2. One technology that has remained relatively unexplored in COVID-19 is the use of antisense oligonucleotides (ASOs)—short single-stranded nucleic acids that bind to target RNA transcripts to modulate their expression.


The COVID-19 pandemic has proven to be one of the greatest global public health challenges of modern times, already claiming the lives of millions of individuals worldwide since the first reported cases in late 2019. Multiple coordinated efforts around the globe have since led to the rapid development and deployment of effective vaccines against SARS-CoV-2, the coronavirus responsible for COVID-19.

Materials and Methods:

Total RNA was extracted from cells or tissue using the miRNeasy mini kit (Qiagen), and cDNA was synthesized from 1 μg total RNA using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems). qPCR was performed using either fast SYBR green master mix or Taqman master mix (Applied Biosystems) on the ViiA7 Real-Time PCR System (Applied Biosystems).


Our previous work showed that infection by SARS-CoV-2 could be attenuated by treatment with AR or BET inhibitors, which decreased expression of the critical host entry factors ACE2 and TMPRSS2. In this study, we explored whether ASOs directly targeting host entry factors or the SARS-CoV-2 genome itself could prevent infection. Several ASOs designed to target ACE2 and SARS-CoV-2 effectively inhibited SARS-CoV-2 infection, including infection by the B.1.1.7 (alpha) variant (Fig 4B). ASOs targeting TMPRSS2 were not as effective at preventing SARS-CoV-2 infection in H1437 cells, but this may be a cell line-dependent observation that should be examined in additional cell lines and lineages.


The following reagents were deposited by Centers for Disease Control and Prevention and obtained through BEI resources, NIAID, NIH: SARS-Related Coronavirus 2, Isolate USA-WA1/2020 (NR-52281) and USA/CA_CDC_5574/2020 (NR-54011).

Citation: Qiao Y, Wotring JW, Zhang CJ, Jiang X, Xiao L, Watt A, et al. (2023) Antisense oligonucleotides to therapeutically target SARS-CoV-2 infection. PLoS ONE 18(2): e0281281.

Editor: Arunava Roy, University of South Florida, UNITED STATES

Received: October 31, 2022; Accepted: January 19, 2023; Published: February 3, 2023.

Copyright: © 2023 Qiao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: J.Z.S. is supported by the National Institute of Diabetes and Kidney Diseases (R01DK120623). J.W.W. is supported by an American Foundation for Pharmaceutical Education (AFPE) regional award. A.M.C. is a Howard Hughes Medical Institute Investigator, A. Alfred Taubman Scholar, and American Cancer Society Professor. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: A.W., D.G., E.S., S.F., E.E.S., and S.G. are employees of Ionis Pharmaceuticals. The remaining authors have no competing interests. We did not receive any financial support from Ionis Pharmaceuticals; they just provided the antisense oligonucleotides for the study (ASOs).

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