# Identification of small molecules for neurological complications of HIV and substance abuse comorbidity

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $740,742

## Abstract

Summary
 HIV-associated neurocognitive disorders (HANDs) and substance abuse comorbidity remain prevalent
despite combination antiretroviral therapy (cART). The innovative hypothesis behind this project is that reversing
trophic deficits that characterize HANDs and manifest as synaptodendritic and mitochondrial injury can
effectively prevent or ameliorate cognitive decline in HIV and compulsive drug taking. To test this hypothesis,
we will perform a throughput screening campaign (HTS) to identify modulators of a newly identified gene
regulatory mechanism that broadly regulates trophic support and mitochondrial biogenesis in key cortical and
hippocampal neuronal populations and that we found are downregulated in both neuroAIDS and dependence.
We expect that small molecules that are able to upregulate this mechanism will make neurons more resilient to
oxidative stress and neurodegeneration, resulting in a reduction of neuronal injury and hypofrontality, which is a
key cause of cognitive dysfunction in HIV and compulsive drug and alcohol taking in dependent individuals. We
will employ cell-based luminescence reporter assays in a 1536-well plate format in conjunction with a tiered
approach to screen the >640,000-compound Scripps Drug Discovery Library (SDDL) and confirm the potency of
~500 drug-like molecules. Hit-validation will be performed to identify small-molecule regulators and eliminate
nonspecific effectors using parallel orthogonal assays and off-target assessment using cytotoxicity
counterscreens employing disease-relevant cell types. To prioritize hit scaffold series, we will select analogs of
confirmed hits from both the existing compound libraries and other commercial sources. Hit scaffolds will be
triaged to remove intractable molecules. We will select 3-5 molecular series from the most promising hits which,
will be profiled to verify the selectivity, potency, and lack of cytotoxicity. Using an orchestrated effort from the
applicant laboratories (Scripps California and Scripps Florida), leads in 2-4 series will be formulated and retested
for potency/selectivity with the aim of advancing leads that can elicit the appropriate in vitro response in the
aforementioned assays and can be evaluated for appropriate phenotypic responses to cell-expression levels.
This will be followed by in vitro and in vivo pharmacokinetics (PK) studies to identify 1-2 top scaffolds for further
investigation. Finally, the most promising 2-3 compounds with favorable drug metabolism and pharmacokinetics
(DMPK) properties will be selected for in vivo testing, including high oral bioavailability, and will be scaled up and
tested in vivo in rodent efficacy models. Efficacy in regulating the expression of the gene expression program
under study will be validated by quantitative polymerase chain reaction of synaptic, dendritic, and mitochondrial
genes and RNA-Seq in conjunction with Gene Set Enrichment Analyses (GSEA). We will then test the ability of
the optimized pro...

## Key facts

- **NIH application ID:** 9850952
- **Project number:** 5R01DA046204-03
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PIETRO P SANNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $740,742
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850952

## Citation

> US National Institutes of Health, RePORTER application 9850952, Identification of small molecules for neurological complications of HIV and substance abuse comorbidity (5R01DA046204-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850952. Licensed CC0.

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