# Chemical Approaches to Control the Function of Regulatory RNAs

> **NIH NIH R35** · STATE UNIVERSITY OF NY,BINGHAMTON · 2022 · $100,980

## Abstract

Recent decades have dramatically changed our view of RNA. While RNA was initially believed to be barely
a passive messenger in the transfer of genetic information from DNA to proteins, it is now clear that RNA is
an exciting and underexplored regulatory molecule that will continue to deliver new discoveries in biology
and medicine. Our research program strives to capitalize on these exciting future discoveries by using
chemical modifications to modulate the structure and function regulatory RNAs. The long-term goals are
to 1) develop novel RNA chemical modifications for fundamental studies and biomedical applications, and
2) explore new modes of sequence-specific recognition of double-stranded RNA (dsRNA). Our research
program comprises two distinct but interrelated projects: 1) amides as novel backbone modifications for
regulatory RNAs, and 2) sequence-specific recognition of dsRNA by modified peptide nucleic acids (PNA).
Project 1 replaces internucleotide phosphates with amide linkages in short interfering RNAs and RNAs
associated with clustered regularly interspaced short palindromic repeats (CRISPR). The goals are to
improve the cellular uptake, delivery and sequence specificity of these RNAs. The premise is that amides
can mimic structure and H-bonding interactions of phosphates with proteins and, at certain positions, may
be able to remodel and improve these interactions. Project 2 explores chemically modified PNA as a ligand
for sequence-specific recognition of biomedically important dsRNA. The goals are to improve the cellular
uptake of PNA and to demonstrate the biological effect of triplex formation using microRNAs as the initial
model system. The premise is that M-modified triplex-forming PNAs are uniquely suited for sequence-
specific recognition of dsRNA and will enable recognition of biologically important non-coding dsRNA.
Future research will focus on chemical modifications of CRISPR RNAs and using the triple helix to control
conformations of complex non-coding RNAs. The projects involve collaborations with structural biochemists
(Martin Egli), biological chemists (Naoki Sugimoto), and a pharmaceutical company (Alnylam). The two
projects share a common theme of designing chemical modifications that take advantage of charge
complementarity between the RNA target and the ligands and proteins interacting with RNA. The
overreaching idea is to develop RNA chemical modifications and RNA binding ligands that avoid
unproductive electrostatic repulsion and capitalize on productive electrostatic attraction while concurrently
enhancing sequence specificity of molecular interactions. This thrust grows out of our recent discoveries
that RNA is unusually receptive to chemical modifications that neutralize the negative charge of phosphate
backbone, both in RNA itself and in RNA binding oligonucleotide analogues. If successful, our research will
contribute to addressing key gaps in RNA interference, CRISPR, recognition of therapeutically relevant...

## Key facts

- **NIH application ID:** 10581333
- **Project number:** 3R35GM130207-04S1
- **Recipient organization:** STATE UNIVERSITY OF NY,BINGHAMTON
- **Principal Investigator:** ERIKS ROZNERS
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $100,980
- **Award type:** 3
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10581333

## Citation

> US National Institutes of Health, RePORTER application 10581333, Chemical Approaches to Control the Function of Regulatory RNAs (3R35GM130207-04S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10581333. Licensed CC0.

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