# Targeting an inactive conformation of HIV-1 TAR

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $234,323

## Abstract

Project Summary
The HIV-1 genome contains highly conserved and structured regulatory RNA elements that
offer unique opportunities to inhibit viral replication in a manner that is potentially less prone
to resistance-conferring mutations as compared to other protein targets. In vivo, the most
attractive HIV-1 RNA drug targets such as TAR and RRE bind to protein assemblies through
large interaction surfaces and strong electrostatic forces. Inhibiting such RNA-protein
interactions using a small molecule presents a significant challenge. In addition, the structure
of TAR and other HIV-1 RNA drug targets are dominated by canonical Watson-Crick helices
that form shallow solvent-exposed binding pockets and limited structural uniqueness. Similar
structures can be found across the human transcriptome. Compounds that bind to these
RNAs frequently bind to other related RNAs and exhibit weak selectivity and/or poor
pharmacological properties. The goal of this project is to advance a new anti-HIV therapeutic
strategy involving inhibition of Tat-dependent transcriptional activation through targeted
stabilization of an inactive conformation of the transactivation response element (TAR) RNA.
The long-term goal of this proposal is to identify drug-like small molecules that selectively
bind and stabilize this inactive TAR conformation, thereby allosterically inhibiting
transcriptional activation and HIV replication. Aim 1 will apply ensemble-based virtual
screening to guide experimetnal screening of 1 million compounds to identify inhibitors of
transcriptional activation and HIV replication that selectively bind TAR and bias the
conformtional equilbrium toward the alternative excited state. Aim 2 will apply structure-
based approaches to further optimize current hits as well as other hits generated in Aim 1
through organic synthesis. If successful, this work will develop a new class of inhibitors of
HIV-1 transcription activation and potentially lay out a new paradigm for targeting RNA based
on stabilization of excited states that can be broadly applied to treat a wide range of
diseases.

## Key facts

- **NIH application ID:** 9941335
- **Project number:** 1R21AI143460-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Hashim M Al-Hashimi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $234,323
- **Award type:** 1
- **Project period:** 2020-02-11 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941335

## Citation

> US National Institutes of Health, RePORTER application 9941335, Targeting an inactive conformation of HIV-1 TAR (1R21AI143460-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9941335. Licensed CC0.

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