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bioRxiv · 10.1101/2021.08.23.457434

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

Li, Y.·Garcia, G.·Arumugaswami, V.·Guo, F.
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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.

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Li, Y., Garcia, G., Arumugaswami, V., Guo, F.. 2021-08-24. Structure-based design of antisense oligonucleotides that inhibit SARS-CoV-2 replication. https://doi.org/10.1101/2021.08.23.457434

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