# Bivalent Ligands as Chemical Probes to Study Opioid Abuse-enhanced HIV Infection

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $567,877

## Abstract

Project Summary
Drug abuse directly contributes to one-third of all HIV infections in the United States. Epidemiological data
have demonstrated that opioid abuse is a significant risk factor for HIV infection and progression to AIDS while
accumulating evidence reveals possible synergistic interactions between the mu opioid (MOR) and CCR5
chemokine receptors in this pathologic process. Therefore, a thorough understanding of the neural pathways
likely involved in opioid enhancement of HIV infection is essential. The putative dimerization of the mu opioid
and CCR5 receptors uniquely affects immune cell function and their molecular interactions may underlie their
apparently synergistic effects in the CNS. Bivalent ligands have been shown to be powerful molecular tools for
characterization of G-protein coupled receptor (GPCR) protein-protein interactions, to interfere with normal
function related to these interactions, or even to treat diseases by targeting such interactions. As a proof-of-
concept, our recently developed bivalent ligand carrying MOR-CCR5 dual antagonist pharmacophores has
shown significantly higher inhibitory effect on HIV-1 invasion in human macrophages and astrocytes compared
to a simple mixture of the two antagonists. Our hypothesis is that bivalent ligands containing both an MOR
antagonist and a CCR5 antagonist may serve as chemical probes to study the interaction of these receptors
with respect to HIV infection enhanced by opioid abuse. We believe a ligand of this kind may serve as a
pharmacological probe to help clarify the molecular mechanism of opioid abuse enhanced HIV infection, and
help establish this evolving protein-protein interaction model as a potential target for therapeutic intervention in
opioid abuse enhanced neuroAIDS. The specific aims of this proposal are to: 1) design and synthesize novel
bivalent ligands containing both an MOR antagonist and a CCR5 antagonist as dual pharmacophores by
applying crystal structures of ligand bound MOR and CCR5 proteins, molecular modeling, and chemical
synthesis; 2) characterize these bivalent ligands with receptor binding and functional assays; and 3) examine
the relative efficacy of bivalent ligands in blocking HIV entry and infectivity via CCR5, and CCR5-MOR
interactions. We believe such an effort will build the foundation to understand such a complicated biological
process, define a novel therapeutic target to treat neuroAIDS, and facilitate future treatment development for
the disease.

## Key facts

- **NIH application ID:** 10169401
- **Project number:** 5R01DA044855-05
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Kurt F Hauser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $567,877
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169401

## Citation

> US National Institutes of Health, RePORTER application 10169401, Bivalent Ligands as Chemical Probes to Study Opioid Abuse-enhanced HIV Infection (5R01DA044855-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169401. Licensed CC0.

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