# Targeting CCR5 Frameshifting with Synthetic Molecules

> **NIH NIH R21** · UNIVERSITY OF ROCHESTER · 2020 · $231,000

## Abstract

Abstract: The human C-C chemokine receptor type 5 (CCR5) is a validated therapeutic target
in HIV, and an important emerging target in a host of additional indications including Chagas
disease, cancer, and liver and kidney fibrosis. While the FDA-approved drug Marviroc has
proven effective as an allosteric inhibitor of CCR5-mediated HIV entry, resistance to Maraviroc
is a known complication. An attractive alternative strategy to allosteric inhibition is to ablate
production of CCR5. It has recently been discovered that translation of CCR5 is subject to a
process known as a -1 programmed ribosomal frameshift, or -1 PRF. In this process, interaction
of the ribosome with a structured portion of the CCR5 mRNA causes it to shift backwards 1
nucleotide. This results in production of a non-functional protein, and triggers degradation of
CCR5 mRNA via nonsense-mediated decay. We hypothesize that compounds able to
specifically bind to and stabilize this structured portion of the CCR5 mRNA, termed a frameshift-
stimulatory sequence, or FSS, will act as frameshift enhancers and constitute a new approach
to inhibiting CCR5 production.
 Our hypothesis is grounded on our success with using an innovative library screening
strategy, termed Resin-Bound Dynamic Combinatorial Chemistry (RBDCC) to identify
compounds able to selectively bind an FSS RNA responsible for frameshifting in HIV. Medicinal
chemistry efforts have resulted in the production of compounds with nanomolar affinity, high
selectivity, and antiviral activity in human cells. We will apply an analogous approach to the
identification of compounds binding the CCR5 FSS RNA, and will develop a new target-
competitive method for RBDCC screening. Libraries will incorporate substituted
diketopiperazines (a privileged substructure in medicinal chemistry), thus addressing an urgent
need for new RNA-binding chemotypes. After prioritizing hit compounds based on biophysical
measurements, including assessment of binding to off-target RNA sequences, a panel of
cellular assays will be employed to assess the ability of CCR5 FSS-targeting compounds to
reduce production of the receptor, and inhibit HIV infectivity. Completion of this research will
provide the first compounds able to influence a human frameshifting event, and proof-of-concept
for a novel CCR5 RNA-targeted therapeutic strategy.

## Key facts

- **NIH application ID:** 9844445
- **Project number:** 5R21AI143494-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Benjamin L Miller
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $231,000
- **Award type:** 5
- **Project period:** 2019-01-03 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844445

## Citation

> US National Institutes of Health, RePORTER application 9844445, Targeting CCR5 Frameshifting with Synthetic Molecules (5R21AI143494-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9844445. Licensed CC0.

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