# Targeting HIV transcription with RNA-binding small molecules

> **NIH NIH R43** · VIRONIKA, LLC · 2022 · $300,000

## Abstract

Summary
 Combination antiretroviral therapy (cART) in current use is able to suppress HIV-1 to
undetectable levels (<50 copies/mL), but unable to eliminate the provirus in latent CD4+ T cells.
Thus, patients must remain under cART indefinitely or risk viral rebound if therapy is discontinued.
The available anti-HIV drugs do not prevent transcription from provirus nor inhibit viral release
from cellular reservoirs. A new class of anti-HIV drugs targeting transcription could buttress
current cART due to its potential to block viral reactivation in latently infected CD4+ T cells,
resulting in a state of deep-latency, followed by the continuous decay of this latent pool of cells
over time. Eradication of the latent HIV reservoir could be achieved by employing disruptors of
HIV’s TAR secondary structure, which would prevent binding of the Tat protein and other host
factors required for transcription. We propose to identify small molecules that specifically bind
and disrupt the apical loop or side bulge in HIV’s TAR hairpin that result in inhibition of the trans-
activation of the viral promoter and virus replication. Vironika LLC has developed new methods
and assays to identify small molecules which interact with structured viral RNA. For example,
Vironika has developed applications of Homogeneous Time-Resolved Fluorescence (HTRF
immunoassay), Alpha Screen (Donor/Acceptor beads) and thermocycler-based Fluorescence
Resonance Energy Transfer (FRET), which enable high-throughput screening (HTS) of small
molecules to identify inhibitors of HSV and EBV latent infection. Libraries containing novel and
proprietary small molecules with potential for new medicinal chemistry will be screened using an
RNA probe representing the TAR hairpin. Cell-based assays will be used to investigate the antiviral
activity of selected hit compounds. The product that ultimately results from this proposal is a
small molecule that selectively binds and disrupts the secondary structure of HIV’s TAR, thereby
inhibiting the binding of TAT and/or P-TEFb which are required for viral expression. Safe,
efficacious, small molecule agents targeting HIV TAR/Tat or TAR/P-TEFb interaction would
inevitably change current clinical practice and possibly enable global control of this disease.

## Key facts

- **NIH application ID:** 10453741
- **Project number:** 5R43AI164984-02
- **Recipient organization:** VIRONIKA, LLC
- **Principal Investigator:** Takahiro Yano
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $300,000
- **Award type:** 5
- **Project period:** 2021-07-20 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453741

## Citation

> US National Institutes of Health, RePORTER application 10453741, Targeting HIV transcription with RNA-binding small molecules (5R43AI164984-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10453741. Licensed CC0.

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