# Molecular Design for Specific Recognition of Functional DNA Sequences

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2021 · $340,875

## Abstract

Project Summary:
Both coding and non-coding DNA genomic sequences as well as their functional significance are becoming
increasingly available. Modulating the functions of these sequences with sequence-specific, cell-permeable
synthetic compounds would be extremely valuable. Deficiency of satisfactory synthetic compounds is a barrier
to applications of our genomic knowledge in biotechnology and drug development. The project described
herein will remove that barrier and will have an impact on human health through the potential for new
anticancer and antiparasitic drugs as well as new biotechnology applications. The project builds on very
successful results in our initial funding period. We found that it is possible to rationally design and prepare
novel modules for both AT and GC base pair (BP) recognition in target DNA sequences. For the first time we
have designed several new heterocyclic, cationic modules which selectively and strongly recognize a single
GC bp with flanking AT sequences. This was a primary goal of our initial proposal and what we propose here
builds from that success. Our design research was initiated with classical types of cell permeable AT specific
minor groove binders that are based on a molecular platform that includes clinically useful compounds. Our
target compounds maintain these features while incorporating new GC recognition modules. The downfall of
most minor groove binders in therapeutics has been lack of sufficient cell and nuclear permeability. Our new
compounds escaped this block but since we wish to target diseases from those induced by cancer to
microorganisms, in Aim 1 we will continue to design, prepare and test new sequence-specific modules for cell
permeability and biological activity. Aim 2 of the proposal describes the preparation of entirely new types of
mixed sequence recognition compounds with our established modules from Aim 1 linked by both serial and
parallel methods to bind tightly and specifically to a broad array of mixed DNA sequences. Preliminary
biophysical findings from our first funding period are a proof of concept that our linked modular design
approach works and can be expanded to more complex sequences in the next funding period. A broad array of
biophysical studies are performed on the new compound-DNA complexes including high resolution NMR
methods and crystallography. Aim 3 is entirely new and was not a part of our initial proposal. It builds on
exciting preliminary results that illustrate important biological functions of our designed compounds. As a test
system, collaborative results with the PU.1 transcription factor (TF) showed that new minor groove agents,
identified in our biosensor in vitro assay, enter cells and nuclei and allosterically inhibit major groove binding
TFs. This important result for future development of an array of TF inhibitors lead to collaborative evaluation of
our compounds against low PU.1 acute myeloid leukemia (AML) patient cells. The compounds entered th...

## Key facts

- **NIH application ID:** 10136608
- **Project number:** 5R01GM111749-08
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** W David Wilson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $340,875
- **Award type:** 5
- **Project period:** 2014-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136608

## Citation

> US National Institutes of Health, RePORTER application 10136608, Molecular Design for Specific Recognition of Functional DNA Sequences (5R01GM111749-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10136608. Licensed CC0.

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