# Mirror Image Aptamers: Next Generation RNA-Binding Reagents for Basic Research and Therapeutic Applications

> **NIH NIH R35** · TEXAS A&M UNIVERSITY · 2020 · $355,929

## Abstract

Project Summary/Abstract
 The increasing appreciation of RNA's structure-function relationship has led to a demand for new
technologies that enable targeting of specific RNA structures. Such technologies are essential for the
development of probes to study RNA function and therapeutics to treat RNA-mediated diseases. However,
outside of antibiotics binding the ribosome, structure-specific RNA-binding reagents are very rare. Thus,
developing of new technologies that enable structure-specific targeting of RNA remains an important challenge
in many fields.
 The central vision of my research program is to address the deficit of structure-specific RNA-binding
reagents using a radically different type of nucleic acid affinity reagent: L-aptamers. L-Aptamers are unique
because they are comprised of L-(deoxy)ribose-based nucleic acids (L-DNA and L-RNA), which are mirror
images (enantiomers) of natural D-nucleotides. Because oligonucleotides of opposite stereochemistry (D
versus L) are incapable of forming contiguous Watson-Crick base pairs with each other, we are able to evolve
L-aptamers that adaptively bind structured D-RNA targets through tertiary interactions (shape) rather than
primary sequence. In other words, L-aptamers escape the tyranny of Watson-Crick base pairing, enabling a
more nuanced mode of molecular recognition to be discovered. As a result, L-aptamers bind structured RNAs
with greater affinity and specificity compared to conventional affinity reagent. Binding RNAs based on their
shape rather than Watson-Crick base pairing represents a significant departure from traditional
oligonucleotide-based approaches and represents a major advance in aptamer technology.
 During the next five year, my research group aims to further develop L-aptamer technology in order to
realize its promise as a practical research and therapeutic tool. In particular, we will focus on incorporation of
modified nucleotides that bestow protein-like functionality on L-aptamers, thus generating a novel class of
RNA-targeted antibody mimetics. Because these technological developments will be carried out in the context
of disease associated RNAs, such as oncogenic microRNAs and viral RNAs, this work will have an immediate
impact by generating lead reagents to probe the etiology of disease and develop new therapeutic strategies. In
line with my vision, we aim to determine the structure of an L-aptamer–D-RNA complex, which will provide
insight into this novel mode of recognition and inform future L-aptamer design.

## Key facts

- **NIH application ID:** 10001546
- **Project number:** 5R35GM124974-04
- **Recipient organization:** TEXAS A&M UNIVERSITY
- **Principal Investigator:** Jonathan Thomas Sczepanski
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,929
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001546

## Citation

> US National Institutes of Health, RePORTER application 10001546, Mirror Image Aptamers: Next Generation RNA-Binding Reagents for Basic Research and Therapeutic Applications (5R35GM124974-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001546. Licensed CC0.

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