Boosting NAD+ with a small molecule that activates NAMPT

Stephen J. Gardell, Meghan Hopf, Asima Khan, Mauro Dispagna, E. Hampton Sessions, Rebecca Falter, Nidhi Kapoor, Jeanne Brooks, Jeffrey Culver, Chris Petucci, Chen Ting Ma, Steven E. Cohen, Jun Tanaka, Emmanuel S. Burgos, Jennifer S. Hirschi, Steven R. Smith, Eduard Sergienko, Anthony B. Pinkerton

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number3241
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    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. (2019). Boosting NAD+ with a small molecule that activates NAMPT. Nature communications, 10(1), [3241]. https://doi.org/10.1038/s41467-019-11078-z