# Targeting SARS-CoV-2 RNA Pseudoknots Using Triplex-Forming Peptide Nucleic Acids

> **NIH NIH R21** · STATE UNIVERSITY OF NY,BINGHAMTON · 2022 · $194,540

## Abstract

SARS-CoV-2, the causative agent of COVID-19, is a positive-sense single-stranded RNA virus in the
Coronaviridae family. The RNA of SARS-CoV-2 folds into complex double-helical structures that open
the door for novel anti-viral approaches targeting RNA instead of proteins. Positive-sense RNA viruses
use the specifically folded RNA structures to highjack the host cell's machinery, regulate viral replication
and mRNA translation, evade antiviral responses, and produce more viral particles. The mechanisms by
which SARS-CoV-2 and other coronaviruses control these processes are not well understood. However,
highly conserved structural motifs of viral RNA, such as pseudoknots and hairpins, are critical for
replication and translation. These motifs act as functional switches of the viral life cycle and are critical
for SARS-CoV-2 pathogenesis. In this application, we propose to use triplex-forming peptide nucleic
acids (PNAs) to control the conformation and biological function of SARS-CoV-2 pseudoknots. The long-
term goals are to (1) better understand SARS-CoV-2 biology and pathogenesis and (2) develop new
and broad-spectrum therapeutics against multiple coronavirus strains. The specific aims are to (1) study
the conformational control of pseudoknot RNA switches with triplex-forming PNA and (2) study how the
PNA binding and RNA switching affects coronavirus biology. We are well positioned to achieve these
Aims because our research group has been working on sequence-specific recognition of biologically
significant RNA molecules using triplex-forming PNAs for more than a decade. The proposed research is
significant and innovative because the biology of dynamic viral RNA switches is poorly understood and
have not been widely targeted in antiviral therapy. Coronaviruses can mutate their RNA genome and
cross species boundaries to infect humans. Therefore, future emergence of new human coronaviruses is
almost guaranteed. Mutated genomes can be rapidly sequenced, allowing us to understand how the
mutations change the structure of regulatory RNA motifs. Novel therapeutic agents targeting structured
RNA motifs will be applicable against multiple strains of coronaviruses and will be easily adjustable for
mutated viruses, which is a key bottleneck for traditional antiviral therapeutics. If SARS-CoV-2 (or
another coronavirus) mutates the PNA target site, all that is needed is to sequence the mutated genome
and change the sequence of therapeutic triplex-forming PNA. RNA is emerging as a major regulatory
molecule in wide variety of biological processes and as a promising novel therapeutic target. Better
understanding of the biological role of viral RNA switches holds tremendous promise to result in
innovative antiviral approaches to combat SARS-CoV-2 and other coronaviruses. If successful, the
proposed research will develop new tools for studying the biology of complex regulatory viral RNAs,
which will have broad and sustained impact on our ability to combat the curr...

## Key facts

- **NIH application ID:** 10328839
- **Project number:** 1R21AI165377-01
- **Recipient organization:** STATE UNIVERSITY OF NY,BINGHAMTON
- **Principal Investigator:** ERIKS ROZNERS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $194,540
- **Award type:** 1
- **Project period:** 2021-11-01 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328839

## Citation

> US National Institutes of Health, RePORTER application 10328839, Targeting SARS-CoV-2 RNA Pseudoknots Using Triplex-Forming Peptide Nucleic Acids (1R21AI165377-01). Retrieved via AI Analytics 2026-07-15 from https://api.ai-analytics.org/grant/nih/10328839. Licensed CC0.

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