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

SUBMITTER: Gardell SJ 

PROVIDER: S-EPMC6642140 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature