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Boosting NAD+ with a small molecule that activates NAMPT
Stephen J Gardell1,2, Meghan Hopf3,4, Asima Khan3,4
1Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, 32827, USA. stephen.gardell@adventhealth.com.
Nature Communications
|July 21, 2019
Summary
Researchers developed SBI-797812, a novel activator of nicotinamide phosphoribosyltransferase (NAMPT), to boost intracellular NAD+. This compound enhances NAMPT
Area of Science:
- Biochemistry
- Cellular Biology
- Pharmacology
Background:
- Boosting intracellular NAD+ is a therapeutic target.
- Nicotinamide phosphoribosyltransferase (NAMPT) is key for NAD+ synthesis.
- Activating NAMPT increases nicotinamide mononucleotide (NMN) production.
Purpose of the Study:
- To identify and characterize novel NAMPT activators.
- To investigate the mechanism of action of SBI-797812.
- To assess the efficacy of SBI-797812 in increasing intracellular NAD+.
Main Methods:
- High-throughput screening for NAMPT activators.
- Hit-to-lead optimization campaign.
- Biochemical assays to determine enzyme kinetics and mechanism.
- Cellular treatment with SBI-797812.
- In vivo studies in mice.
Main Results:
- SBI-797812 was identified as a NAMPT activator.
- SBI-797812 enhances NAMPT activity by shifting equilibrium, increasing ATP affinity, stabilizing the enzyme, and reducing feedback inhibition.
- SBI-797812 treatment increased intracellular NMN and NAD+ levels in cultured cells.
- SBI-797812 administration elevated liver NAD+ levels in mice.
Conclusions:
- SBI-797812 acts as a potent NAMPT activator, transforming it into a 'super catalyst'.
- This pioneering approach effectively raises intracellular NAD+ levels.
- Small molecule NAMPT activators hold therapeutic potential for conditions associated with NAD+ deficiency.
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