Boosting NAD+ with a small molecule that activates NAMPT
Open accessAbstract
Pharmacological strategies that boost intracellular NAD + are highly coveted for their therapeutic potential. One approach is activation of nicotinamide phosphoribosyltransferase (NAMPT) to increase production of nicotinamide mononucleotide (NMN), the predominant NAD + precursor in mammalian cells. A high-throughput screen for NAMPT activators and hit-to-lead campaign yielded SBI-797812, a compound that is structurally similar to active-site directed NAMPT inhibitors and blocks binding of these inhibitors to NAMPT. SBI-797812 shifts the NAMPT reaction equilibrium towards NMN formation, increases NAMPT affinity for ATP, stabilizes phosphorylated NAMPT at His247, promotes consumption of the pyrophosphate by-product, and blunts feedback inhibition by NAD + . These effects of SBI-797812 turn NAMPT into a “super catalyst” that more efficiently generates NMN. Treatment of cultured cells with SBI-797812 increases intracellular NMN and NAD + . Dosing of mice with SBI-797812 elevates liver NAD + . Small molecule NAMPT activators such as SBI-797812 are a pioneering approach to raise intracellular NAD + and realize its associated salutary effects.
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SBI-797812 had a limited effect of boosting only hepatic NAD+ levels in vivo.
“Despite the limited effect of SBI-797812 of boosting only hepatic NAD+ levels in vivo”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [215]
SBI-797812 is a potent NAMPT activator active in the nanomolar range; it increased NAMPT-mediated NMN production in vitro and NAD+ levels in cell lines and in vivo.
“SBI-797812, was proposed as a potent NAMPT activator active in the nanomolar range. This compound increased NAMPT-mediated NMN production in vitro and, importantly, NAD+ levels in cell lines and in vivo214,215.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [215]
The real efficacy of P7C3 in increasing NAMPT activity remains controversial.
“the real efficacy of P7C3 in increasing NAMPT activity remains controversial215.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [215]
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References 31 · Cited by 169
- Authors
- Gardell, S. J., Hopf, M., Khan, A., Dispagna, M., Hampton Sessions, E., Falter, R., Kapoor, N., Brooks, J., Culver, J., Petucci, C., Ma, C.-T., Cohen, S. E., Tanaka, J., Burgos, E. S., Hirschi, J. S., Smith, S. R., Sergienko, E., & Pinkerton, A. B.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Daiichi Sankyo (United States) (US)
- Daiichi-Sankyo (Japan) (JP)
- Albert Einstein College of Medicine (US)
- Binghamton University (US)
- Corresponding author
- Gardell, Stephen J.
- Pinkerton, Anthony B.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-07-19
- Volume
- 10
- Issue
- 1
- Pages
- 3241-3241
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6642140
- OpenAlex
- W2963580194
- Cited by
- 169
- References
- 31
- Citations by year
- 2026: 16 · 2025: 27 · 2024: 30 · 2023: 28 · 2022: 25 · 2021: 22 · 2020: 19 · 2019: 1
- FWCI
- 9.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (ACI-1 548 562, 1548562)
- Florida Department of Health (COHK8)
- National Institutes of Health (1548562, ACI-1548562, DK097209)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK097209)
- Daiichi Sankyo Europe
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- NAD+, nicotinamide mononucleotide, NAMPT inhibitors, NAD+ precursors, small molecule activators
- MeSH terms
- A549 Cells, Animals, Humans, Liver, NAD, Nicotinamide Mononucleotide, Phosphorylation, Molecular Structure, Enzyme Activators, Intracellular Space, Mice, Nicotinamide Phosphoribosyltransferase, Small Molecule Libraries, Biocatalysis
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