Boosting NAD+ with a small molecule that activates NAMPT
| Autor: | Jun Tanaka, Emmanuel S. Burgos, Rebecca Falter, E. Hampton Sessions, Jeanne Brooks, Stephen J. Gardell, Steven E. Cohen, Anthony B. Pinkerton, Asima Khan, Jennifer S. Hirschi, Meghan E. Hopf, Nidhi Kapoor, Jeffrey A. Culver, Chris Petucci, Steven R. Smith, Eduard Sergienko, Chen Ting Ma, Mauro Dispagna |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
A549 cell Multidisciplinary Activator (genetics) Chemistry Science Nicotinamide phosphoribosyltransferase General Physics and Astronomy 02 engineering and technology General Chemistry 021001 nanoscience & nanotechnology Small molecule General Biochemistry Genetics and Molecular Biology Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Phosphorylation lcsh:Q NAD+ kinase lcsh:Science 0210 nano-technology Intracellular Nicotinamide mononucleotide |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-11078-z |
| Popis: | 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. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate determining step for NAD+ synthesis and is of interest as a drug target. Here the authors identify and characterize a small molecule NAMPT activator SBI-797812, elucidate its mode of action and show that it increases intracellular NMN and NAD+ levels in cultured cells and elevates liver NAD+ in mice. |
| Databáze: | OpenAIRE |
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