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 and Anthony B. Pinkerton ()
Additional contact information
Stephen J. Gardell: Sanford Burnham Prebys Medical Discovery Institute at Lake Nona
Meghan Hopf: Sanford Burnham Prebys Medical Discovery Institute at Lake Nona
Asima Khan: Sanford Burnham Prebys Medical Discovery Institute at Lake Nona
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
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
Eduard Sergienko: Sanford Burnham Prebys Medical Discovery Institute
Anthony B. Pinkerton: Sanford Burnham Prebys Medical Discovery Institute

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11078-z

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