Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-11078-z
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Funding
- Florida Translational Research Program
- NIH [U24 DK097209]
- NSF [ACI1548562]
- Daiichi Sankyo Co. Ltd.
- SBP
- AdventHealth
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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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