# Improving healthspan through discovery of potent NAMPT activators from a DNA-encoded library

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $205,806

## Abstract

Abstract
Advancing age is a primary risk factor for numerous chronic diseases including cardiovascular and metabolic
diseases, as well as sarcopenia. Increasing evidence suggests that the levels of the cofactor NAD+ and the
activity of NAD+-dependent proteins such as sirtuins have close links to the process of aging and development
of chronic diseases. While many studies exploring the health benefit of nutritional supplementation with sirtuin
activators and NAD+-precursors have had encouraging preclinical results, there are currently no drug
candidates that directly act on NAD+-metabolism. The objective of the proposed research project is to develop
a potent activator of nicotinamide phosphorybosyltransferase (NAMPT), the enzyme that catalyzes the rate
limiting step in NAD+ synthesis, and to evaluate its ability to reverse age-related physiological dysfunction in a
preclinical mouse model. Although previous studies have established that NAMPT activation can have age-
delaying and disease-preventing effects, no currently available therapeutics are directed at modulating NAMPT
activity per se. The proposed research addresses the key limitation towards accessing such drug candidates,
which is the lack of a potent, selective, and mechanistically validated lead molecules for NAMPT activation with
a favorable absorption, distribution, metabolism and excretion (ADME) profile. To access such a compound, in
the R21 phase of this application, we propose to develop and screen a NAMPT-focused DNA-encoded
chemical library and to use computational drug discovery methods to advance screening hits into potent lead
candidate compounds. The efficacy of NAMPT activators will be tested with in vitro assays and in three
different cell lines. Once candidate compounds are identified, the R33 phase will consist, first of
comprehensive pharmacokinetic studies in lead candidate compounds to determine the appropriate dose and
route of administration for in vivo studies. The lead compound will then be utilized to assess the impact of
treatment on physiological measures of healthspan in middle-aged and old mice. The project, if successful, will
deliver preclinical lead compounds for the development of first-in-class therapeutics that directly target the
aging-related pathways of a wide range of chronic diseases. In the long term, such drugs may help decrease
the morbidity and mortality of geriatric patients.

## Key facts

- **NIH application ID:** 10464159
- **Project number:** 1R21AG074498-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Anthony John Donato
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $205,806
- **Award type:** 1
- **Project period:** 2022-09-05 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464159

## Citation

> US National Institutes of Health, RePORTER application 10464159, Improving healthspan through discovery of potent NAMPT activators from a DNA-encoded library (1R21AG074498-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464159. Licensed CC0.

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