# Developing three-dimensional antisense oligonucleotide drugs against COVID-19

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $426,633

## Abstract

Project Summary (Abstract)
Developing three-dimensional antisense oligonucleotide drugs against COVID-19
The culprit of coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome-related
coronavirus-2 (SARS-CoV-2), has a very large RNA genome that encodes the proteins and RNA elements
required for all aspects of viral infection and replication. This property makes the virus vulnerable to a new class
of drugs called antisense oligonucleotide (ASO). ASOs are single-stranded synthetic nucleic acids that achieve
therapeutic effects by binding to viral or other target RNAs via Watson-Crick base pairing, the very interaction
that defines molecular biology and the foundation of life. The first ASO drug approved by the U.S. Food and Drug
Administration is an antiviral against cytomegalovirus. A major challenge of developing ASO antiviral drugs is
the strong tendency of RNA to fold into structures that interfere with ASO hybridization. Current ASO design
methods do not adequately address this problem.
We have developed a structure-based ASO design technology platform that takes advantage of three-
dimensional structures of target RNAs. Our “3D-ASOs” recognize not only the sequences but also the shapes of
SARS-CoV-2 RNAs. Compared to conventional designs, 3D-ASOs contact viral RNAs more extensively and
therefore can achieve greater affinity and specificity. Our technology platform includes four design templates and
a 3D-ASO drug development workflow that employs an innovative RNA structure determination method. In a
preliminary study, we designed and tested several 3D-ASOs against SARS-CoV-2 viral RNA and identified two
lead sequences that strongly inhibit viral replication in cultured human cells to a much greater extent than
previously reported sequences. In the proposed research, we will optimize the lead 3D-ASOs by altering their
backbone modifications and bases for tighter binding and better fit to the viral RNAs and for stronger inhibition
to their functions. We will also cast our net wide by designing and testing additional anti-SARS-CoV-2 3D-ASOs.
Finally, the most potent 3D-ASOs will be tested in an animal model. If successful, the project will provide ASO
drug candidates for clinical trials. These drugs may be given as nasal sprays or via intravenous injection, as
treatments or for prevention. The structure-based design technology we will refine is generally applicable to ASO
drug development. Therefore, this research has the potential to turn tide on the battlefield against COVID-19 and
in our fight with many other diseases.

## Key facts

- **NIH application ID:** 10280762
- **Project number:** 1R01AI163216-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Feng Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $426,633
- **Award type:** 1
- **Project period:** 2021-07-19 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10280762

## Citation

> US National Institutes of Health, RePORTER application 10280762, Developing three-dimensional antisense oligonucleotide drugs against COVID-19 (1R01AI163216-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10280762. Licensed CC0.

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