PT  - JOURNAL ARTICLE
AU  - Li, Yan
AU  - Garcia, Gustavo
AU  - Arumugaswami, Vaithilingaraja
AU  - Guo, Feng
TI  - Structure-based design of antisense oligonucleotides that inhibit SARS-CoV-2 replication
AID  - 10.1101/2021.08.23.457434
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.23.457434
4099  - http://biorxiv.org/content/early/2021/08/24/2021.08.23.457434.short
4100  - http://biorxiv.org/content/early/2021/08/24/2021.08.23.457434.full
AB  - 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 StatementA 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.