# Allosteric Modulators of Dopamine Transporter as Therapeutic Agents for NeuroAIDS

> **NIH NIH R01** · SOUTHERN RESEARCH INSTITUTE · 2020 · $805,690

## Abstract

PROJECT SUMMARY
 More than 37 million people are living with Human Immunodeficiency Virus (HIV) infection worldwide which
continues to be a global public health problem. Despite the widespread use of antiretroviral therapy (ART), up to
70% of HIV-positive individuals suffer from cognitive and behavioral deficits collectively known as HIV-associated
neurocognitive disorders (HAND), for which no therapeutic options are currently available. Converging lines of
evidence indicate that the HIV-1 transactivator of transcription (Tat) protein plays a crucial role in causing
neurotoxicity and cognitive impairment in HAND. HIV-1 Tat exerts its neurotoxicity through interaction with crucial
proteins, such as the monoamine transporters in the central nervous system (CNS). The dysregulation of
dopamine (DA) neurotransmission in HAND occurs through direct interaction of Tat protein with the DA
transporter (DAT) which is essential for maintaining DA homeostasis and a target of cocaine. While most ARTs
cannot efficiently cross the blood-brain barrier, Tat-induced increase in DA levels accelerates viral replication in
the brain. Moreover, drugs of abuse, such as cocaine, exacerbate neurological impairments. Our published work
has demonstrated that Tat-induced inhibition of DAT is mediated by binding of Tat to allosteric binding site(s) on
DAT, not by interacting with the DA uptake site. This provides a basis for a novel approach to address the
problem by developing compounds to attenuate Tat binding to DAT by an allosteric mechanism. Our recent
studies with small molecule allosteric ligands of DAT reveal that these compounds are capable of attenuating
Tat-mediated effects on DAT, thus providing a potential opportunity to develop therapeutic interventions for the
treatment of HAND. The research effort proposed herein is to explore the hypothesis that disruption of Tat-DAT
interactions with small molecule allosteric ligands of DAT, with minimal disruption of normal DA uptake, will have
therapeutic potential for prevention of neurocognitive dysfunction in HAND. The primary goal of our research is
to optimize lead compounds and perform proof-of-concept pharmacological studies in animal models. To this
end, the specific aims to be pursed in the proposed effort are to: (1) design and synthesize novel allosteric
ligands with improved physicochemical and pharmacokinetic properties using in silico property predictions and
computational docking studies with DAT-Tat complex models, (2) characterize the allosteric interaction of the
compounds with human DAT in vitro to identify optimized compounds with improved physicochemical properties
that can be used to alleviate Tat-induced dysfunction of DAT, and (3) determine the efficacy of selected
compounds in attenuating Tat-mediated cognitive deficits and rewarding effects of cocaine in inducible Tat
transgenic mice in vivo. This collaborative effort involves investigators with complementary expertise in medicinal
chemistry, drug...

## Key facts

- **NIH application ID:** 9927153
- **Project number:** 1R01DA047924-01A1
- **Recipient organization:** SOUTHERN RESEARCH INSTITUTE
- **Principal Investigator:** CORINNE ELIZABETH AUGELLI-SZAFRAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $805,690
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927153

## Citation

> US National Institutes of Health, RePORTER application 9927153, Allosteric Modulators of Dopamine Transporter as Therapeutic Agents for NeuroAIDS (1R01DA047924-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9927153. Licensed CC0.

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