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Boosting NAD+ with a small molecule that activates NAMPT

Author

Listed:
  • Stephen J. Gardell

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona
    AdventHealth-Orlando)

  • Meghan Hopf

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona
    AdventHealth-Orlando)

  • Asima Khan

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona
    AdventHealth-Orlando)

  • Mauro Dispagna

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona)

  • E. Hampton Sessions

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona)

  • Rebecca Falter

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona)

  • Nidhi Kapoor

    (AdventHealth-Orlando
    Sanford Burnham Prebys Medical Discovery Institute at Lake Nona)

  • Jeanne Brooks

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona)

  • Jeffrey Culver

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona)

  • Chris Petucci

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona)

  • Chen-Ting Ma

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Steven E. Cohen

    (Global Business Development)

  • Jun Tanaka

    (Ltd, Shinagawa Research & Development Center)

  • Emmanuel S. Burgos

    (Albert Einstein College of Medicine)

  • Jennifer S. Hirschi

    (Binghamton University)

  • Steven R. Smith

    (Sanford Burnham Prebys Medical Discovery Institute at Lake Nona
    AdventHealth-Orlando)

  • Eduard Sergienko

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Anthony B. Pinkerton

    (Sanford Burnham Prebys Medical Discovery Institute)

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.

Suggested Citation

  • 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 &, 2019. "Boosting NAD+ with a small molecule that activates NAMPT," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11078-z
    DOI: 10.1038/s41467-019-11078-z
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    Cited by:

    1. Nicholas Sim & Jean-Michel Carter & Kamalakshi Deka & Benita Kiat Tee Tan & Yirong Sim & Suet-Mien Tan & Yinghui Li, 2024. "TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Björn Klabunde & André Wesener & Wilhelm Bertrams & Isabell Beinborn & Nicole Paczia & Kristin Surmann & Sascha Blankenburg & Jochen Wilhelm & Javier Serrania & Kèvin Knoops & Eslam M. Elsayed & Katri, 2023. "NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Liang Yang & Junfeng Shen & Chunhua Liu & Zhonghua Kuang & Yong Tang & Zhengjiang Qian & Min Guan & Yongfeng Yang & Yang Zhan & Nan Li & Xiang Li, 2023. "Nicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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