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Boosting NAD with a small molecule that activates NAMPT

Nature Communications, ISSN: 2041-1723, Vol: 10, Issue: 1, Page: 3241
2019
  • 116
    Citations
  • 0
    Usage
  • 144
    Captures
  • 0
    Mentions
  • 1
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    116
  • Captures
    144
  • Social Media
    1
    • Shares, Likes & Comments
      1
      • Facebook
        1

Article Description

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.

Bibliographic Details

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

Springer Science and Business Media LLC

Chemistry; Biochemistry, Genetics and Molecular Biology; Physics and Astronomy

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