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

doi:10.1038/s41467-019-11078-z

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

Biochemistry

Research output: Contribution to journal › Article › peer-review

76 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 language	English (US)
Article number	3241
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11078-z
State	Published - Dec 1 2019

ASJC Scopus subject areas

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

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10.1038/s41467-019-11078-z

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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), Article 3241. https://doi.org/10.1038/s41467-019-11078-z

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title = "Boosting NAD+ with a small molecule that activates NAMPT",

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.",

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

note = "Funding Information: We thank the Protein Expression and Purification core (D. Kuijstermans, G. Seo) at SBP in Orlando for producing human NAMPT, mouse NAMPT and human NMNAT1. We are indebted to the SBP Metabolomics core (N.K., J.B., J.C., C.P., and A. Zelenin) for their assistance. Heavy isotope labeled NMN and NAD+ were prepared by D. Divianska and E.H.S. of the CPCCG at SBP in Orlando (partially supported by Florida Translational Research Program, a contract administered by the Florida Department of Health (COHK8)). The Metabolomics core at SBP, which is partnered with the Southeast Center for Integrated Metabolomics (SECIM) was partially supported by NIH grant U24 DK097209 (S.J.G.). Computational support was provided by XSEDE (Extreme Science and Engineering Discovery Environment) and supported by NSF grant number ACI-1548562 (J.S.H.). Funding for this project was provided by SBP, AdventHealth and Daiichi Sankyo Co. Ltd. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

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doi = "10.1038/s41467-019-11078-z",

language = "English (US)",

volume = "10",

journal = "Nature communications",

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T1 - Boosting NAD+ with a small molecule that activates NAMPT

AU - Gardell, Stephen J.

AU - Hopf, Meghan

AU - Khan, Asima

AU - Dispagna, Mauro

AU - Hampton Sessions, E.

AU - Falter, Rebecca

AU - Kapoor, Nidhi

AU - Brooks, Jeanne

AU - Culver, Jeffrey

AU - Petucci, Chris

AU - Ma, Chen Ting

AU - Cohen, Steven E.

AU - Tanaka, Jun

AU - Burgos, Emmanuel S.

AU - Hirschi, Jennifer S.

AU - Smith, Steven R.

AU - Sergienko, Eduard

AU - Pinkerton, Anthony B.

N1 - Funding Information: We thank the Protein Expression and Purification core (D. Kuijstermans, G. Seo) at SBP in Orlando for producing human NAMPT, mouse NAMPT and human NMNAT1. We are indebted to the SBP Metabolomics core (N.K., J.B., J.C., C.P., and A. Zelenin) for their assistance. Heavy isotope labeled NMN and NAD+ were prepared by D. Divianska and E.H.S. of the CPCCG at SBP in Orlando (partially supported by Florida Translational Research Program, a contract administered by the Florida Department of Health (COHK8)). The Metabolomics core at SBP, which is partnered with the Southeast Center for Integrated Metabolomics (SECIM) was partially supported by NIH grant U24 DK097209 (S.J.G.). Computational support was provided by XSEDE (Extreme Science and Engineering Discovery Environment) and supported by NSF grant number ACI-1548562 (J.S.H.). Funding for this project was provided by SBP, AdventHealth and Daiichi Sankyo Co. Ltd. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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Boosting NAD⁺ with a small molecule that activates NAMPT

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