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.

Details

Title
Boosting NAD+ with a small molecule that activates NAMPT
Author
Gardell, Stephen J 1 ; Hopf, Meghan 1 ; Khan, Asima 1 ; Dispagna, Mauro 2 ; E Hampton Sessions 3 ; Falter, Rebecca 3 ; Kapoor, Nidhi 4 ; Brooks, Jeanne 5 ; Culver, Jeffrey 5 ; Petucci, Chris 5 ; Chen-Ting, Ma 6 ; Cohen, Steven E 7   VIAFID ORCID Logo  ; Tanaka, Jun 8   VIAFID ORCID Logo  ; Burgos, Emmanuel S 9   VIAFID ORCID Logo  ; Hirschi, Jennifer S 10 ; Smith, Steven R 1 ; Sergienko, Eduard 6 ; Pinkerton, Anthony B 6 

1  Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA; Translational Research Institute for Metabolism and Diabetes, AdventHealth-Orlando, Orlando, FL, USA 
2  Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA 
3  Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA 
4  Translational Research Institute for Metabolism and Diabetes, AdventHealth-Orlando, Orlando, FL, USA; Metabolomics Core Facility, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA 
5  Metabolomics Core Facility, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA 
6  Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA 
7  Daiichi Sankyo, Inc., Global Business Development, Basking Ridge, NJ, USA 
8  Daiichi Sankyo Co., Ltd, Shinagawa Research & Development Center, Tokyo, Japan 
9  Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA 
10  Department of Chemistry, Binghamton University, Binghamton, NY, USA 
Pages
1-12
Publication year
2019
Publication date
Jul 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-11078-z
ProQuest document ID
2260416750
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.