# Novel allosteric activation of nicotinamide rescue

> **NIH NIH RF1** · UNIVERSITY OF ARIZONA · 2020 · $2,264,368

## Abstract

ABSTRACT
Aging is the single most significant risk factor for Alzheimer’s disease and related dementia (ADRD), leading to
consideration of new therapeutic approaches from the field of Geroscience, such as nicotinamide adenine
dinucleotide (NAD+) enhancing dietary supplements that exhibit anti-aging properties and improve lifespan and
healthspan in rodents. Maintaining levels of NAD, a central metabolic cofactor in eukaryotic cells that plays a
critical role in electron transfer, cellular metabolism, and energy homeostasis, relies in mammals on the salvage
of nicotinamide (NAM) by the enzyme nicotinamide phosphoribosyltransferase (NAMPT). NAD is catabolized to
NAM by PARPs, sirtuins, and CD38; systems that are upregulated to counteract DNA damage and cellular stress
with aging. A decline in the NAD pool plays a crucial role in the aging brain, by increasing mitochondrial
dysfunction and various age-related pathologies including enhanced oxidative stress, inflammation and impaired
insulin sensitivity. We have discovered a unique NAMPT allosteric site, supported by co-crystal structures
of NAMPT positive allosteric modulators (N-PAMs), and plan to optimize these as chemical probes. We
hypothesize a N-PAM that selectively activates NAMPT in the brain, increasing NAM turnover and attenuating
ATP consumption, will ameliorate the age-related loss of NAD that combines with AD pathology in the
pathogenesis ADRD. In Aim 1 we will optimize N-PAM using our HTS coupled-enzyme assay and supporting
biochemical assays, with a focus on properties driving brain bioavailability. Three hit series have been identified
with nanomolar potency and affinity and 1.3-1.5A co-crystal structures obtained. In Aim 2 we will use cell-based
phenotypic and target engagement assays to test NMN and NAD levels, mitochondrial rescue, and
neuroprotection. NAD dietary supplementation (NMN, NR, NAD) has been studied in models of familial AD
(FAD)-Tg and Type 2 diabetes (T2D), including the T2D model of mice on high fat diet (HFD). This HFD/T2D
model is the simplest route to determine PK/PD relationships for N-PAMs. Therefore, in Aim 3 we will measure
NAD metabolome, insulin sensitivity, and glucose metabolism in HFD mice to derive an efficacious oral dose
from PK/PD for an optimized brain bioavailable N-PAM. The effect on behavior, AD pathology, and biomarkers
will be studied in male vs. female FAD-Tg mice carrying human APOE3/APOE4. The N-PAM chemical probe
will be suitable for future studies to determine: effects in aged animals (alone and in combination with e.g. NAM
and NMNAT upregulation); and detailed effects on cellular processes such mitophagy and misfolded protein
clearance. N-PAM probes are leads for therapeutic agent development for ADRD and T2D. The team includes
experts in drug discovery, ADRD, and T2D.

## Key facts

- **NIH application ID:** 9998524
- **Project number:** 1RF1AG067771-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Gregory R. J Thatcher
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,264,368
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998524

## Citation

> US National Institutes of Health, RePORTER application 9998524, Novel allosteric activation of nicotinamide rescue (1RF1AG067771-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9998524. Licensed CC0.

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