# Early development of small molecule neuroprotectants.

> **NIH NIH R01** · SCRIPPS FLORIDA · 2021 · $733,123

## Abstract

SUMMARY
NAD depletion occurs after excitotoxic insults and oxidative stress and causes neuronal death in several
rodent models of neurodegenerative conditions, including models for brain ischemia/reperfusion injury and
Wallerian degeneration. We have recently discovered that NAD depletion is also the primary cause of
neuronal death induced by exposure to a misfolded and toxic form of the amyloidogenic prion protein
(TPrP). NAD replenishment reversed the fate of TPrP-injured neurons in culture and improved motor
function in a mouse model of prion disease. Therefore, our study established NAD restoration as a new
therapeutic target for protein misfolding neurodegenerative diseases, a family of diseases that includes
Alzheimer's, Parkinson's, prion diseases and amyotrophic lateral sclerosis (ALS). We developed a high-
throughput screening strategy to identify NAD-dependent neuroprotective small molecules in the misfolded
protein toxicity paradigm and then conducted a screening campaign. We identified and selected four
chemical series providing complete neuroprotection and preserving NAD levels with nanomolar potency.
One compound was tested in a murine model of ALS and improved the mice's muscle strength and motor
function. We will conduct molecular mode of action studies for each chemical series, in conjunction with
potency and drug metabolism and pharmacokinetic (DMPK) studies, to guide selection of the top lead. Lead
optimization will be done through iterative rounds of structure-activity relationship studies and subjecting
analogs to a series of in vitro and in vivo assays for potency, selectivity and absence of undesired off-target
effects, as well as favorable DMPK properties including brain penetration. This workplan will deliver a novel
small molecule neuroprotectant poised for investigational new drug (IND)–enabling studies and ultimately
for the treatment of neurological conditions linked to a deficit in NAD.

## Key facts

- **NIH application ID:** 10241448
- **Project number:** 5R01NS103195-04
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Thomas D Bannister
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $733,123
- **Award type:** 5
- **Project period:** 2018-08-15 → 2022-04-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241448

## Citation

> US National Institutes of Health, RePORTER application 10241448, Early development of small molecule neuroprotectants. (5R01NS103195-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241448. Licensed CC0.

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