# Targeting Nucleic Acids with an Integrated Virtual and Actual Screen

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2020 · $355,395

## Abstract

We seek a second renewal for our program to refine and apply an integrated virtual and actual screening
platform for the discovery of new lead compounds to inhibit telomerase. Progress during the current funding
period was outstanding, and we have achieved most of the specific aims proposed. During the next funding
period, we will focus on the discovery of lead compounds that bind selectively to biologically important higher-
order telomeric DNA quadruplexes and targeting the single strand telomere:POT1 interface. Telomerase has
been identified as a target for over 20 years, but there are no approved drugs that inhibit its activity, so new
approaches are required. We will inhibit POT1 (Protection of Telomere 1), a protein essential for telomerase
activity, by targeting the telomeric DNA substrate, and by directly targeting the POT1 telomeric DNA binding
function. We now propose fundamental studies that will continue to develop and refine our integrated
screening platform.
 Nucleic acids remain underrepresented targets for small molecule therapeutic agents. There is mounting
evidence to indicate that non-B DNA structures play prominent roles in gene expression and especially in the
function of telomeres. Targeting these structural elements is an attractive and innovative strategy for the
development of new therapeutic agents. The higher-order DNA quadruplex structures formed by the single
strand of the human telomere remain a very poorly and improperly investigated target as traditional structural
biology approaches have been unsuccessful. We have used a combination of computational modeling and
experimental biophysics to derive consistent structural models for telomeric DNA sequences of up to 192
bases, or eight quadruplex repeats, in the current grant period. The higher-order quadruplex stacking
interfaces thus represent a new target for small molecule stabilization of telomeric DNA. This stabilization
should inhibit telomerase by locking the substrate DNA in an unusable form. An even more under represented
target than non-B DNA is the nucleic acid-protein interaction, particularly single stranded DNA:protein
complexes, as exist with POT1. We will target both the DNA substrate and the DNA-binding function of POT1,
which could lead to synergistic inhibition of telomerase. This is a natural progression from our current funding
period where we targeted biologically relevant quadruplex structures, to telomere-like higher-order quadruplex
nucleic acid structures and the telomere ssDNA binding protein POT1, which is essential for telomeric DNA
replication. The Specific Aims are: 1) Targeting higher-order telomeric quadruplex structures using integrated
virtual and actual screens; 2) Characterizing the specific interactions of POT1 with higher-order quadruplexes;
3) Targeting POT1 using integrated virtual and actual screens; 4) Characterizing the biological properties of
higher-order G-quadruplexes and POT1 binding agents.
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## Key facts

- **NIH application ID:** 9918887
- **Project number:** 5R01GM077422-11
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Jonathan B. CHAIRES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,395
- **Award type:** 5
- **Project period:** 2007-02-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918887

## Citation

> US National Institutes of Health, RePORTER application 9918887, Targeting Nucleic Acids with an Integrated Virtual and Actual Screen (5R01GM077422-11). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9918887. Licensed CC0.

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