# Allosteric Modulators of Dopamine Transporter as Therapeutic Agents for NeuroAIDS

> **NIH NIH R01** · SOUTHERN RESEARCH INSTITUTE · 2023 · $148,255

## Abstract

Project Summary/Abstract
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 chemis...

## Key facts

- **NIH application ID:** 10756629
- **Project number:** 3R01DA047924-04S1
- **Recipient organization:** SOUTHERN RESEARCH INSTITUTE
- **Principal Investigator:** CORINNE ELIZABETH AUGELLI-SZAFRAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $148,255
- **Award type:** 3
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756629

## Citation

> US National Institutes of Health, RePORTER application 10756629, Allosteric Modulators of Dopamine Transporter as Therapeutic Agents for NeuroAIDS (3R01DA047924-04S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10756629. Licensed CC0.

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