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Structure-based design of antisense oligonucleotides that inhibit SARS-CoV-2 replication

Yan Li, View ORCID ProfileGustavo Garcia Jr, Vaithilingaraja Arumugaswami, View ORCID ProfileFeng Guo
doi: https://doi.org/10.1101/2021.08.23.457434
Yan Li
1Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, U.S.A
2Molecular Biology Interdepartmental Ph.D. Program, University of California, Los Angeles, CA 90095, U.S.A
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Gustavo Garcia Jr
3Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, U.S.A
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Vaithilingaraja Arumugaswami
3Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, U.S.A
4Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, U.S.A
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  • For correspondence: fguo@mbi.ucla.edu varumugaswami@mednet.ucla.edu
Feng Guo
1Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, U.S.A
5Molecular Biology Institute, University of California, Los Angeles, CA 90095, U.S.A
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  • For correspondence: fguo@mbi.ucla.edu varumugaswami@mednet.ucla.edu
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ABSTRACT

Antisense oligonucleotides (ASOs) are an emerging class of drugs that target RNAs. Current ASO designs strictly follow the rule of Watson-Crick base pairing along target sequences. However, RNAs often fold into structures that interfere with ASO hybridization. Here we developed a structure-based ASO design method and applied it to target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our method makes sure that ASO binding is compatible with target structures in three-dimensional (3D) space by employing structural design templates. These 3D-ASOs recognize the shapes and hydrogen bonding patterns of targets via tertiary interactions, achieving enhanced affinity and specificity. We designed 3D-ASOs that bind to the frameshift stimulation element and transcription regulatory sequence of SARS-CoV-2 and identified lead ASOs that strongly inhibit viral replication in human cells. We further optimized the lead sequences and characterized structure-activity relationship. The 3D-ASO technology helps fight coronavirus disease-2019 and is broadly applicable to ASO drug development.

Competing Interest Statement

A provisional patent (application # 63226617) has been filed by UCLA and is currently pending. F.G. and V.A. are the inventors. The authors have no other competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 24, 2021.
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Structure-based design of antisense oligonucleotides that inhibit SARS-CoV-2 replication
Yan Li, Gustavo Garcia Jr, Vaithilingaraja Arumugaswami, Feng Guo
bioRxiv 2021.08.23.457434; doi: https://doi.org/10.1101/2021.08.23.457434
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Structure-based design of antisense oligonucleotides that inhibit SARS-CoV-2 replication
Yan Li, Gustavo Garcia Jr, Vaithilingaraja Arumugaswami, Feng Guo
bioRxiv 2021.08.23.457434; doi: https://doi.org/10.1101/2021.08.23.457434

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