Volume 32, No 6, Jun 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 6, June 2022: 570-584

ORIGINAL ARTICLES

Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity

Hong Yao^1,2,† , Minghui Liu^1,† , Leibo Wang^1,† , Yumeng Zu^1,† , Chou Wu^1,3,† , Chenyu Li¹ , Ruoxi Zhang¹ , Haigen Lu⁴ , Feifei Li¹ , Shuang Xi¹ , Shuangquan Chen¹ , Xuanyu Gu¹ , Tianya Liu⁵ , Jie Cai⁶ , Shirong Wang⁷ , Maojun Yang⁵ , Guo-Gang Xing⁶ , Wei Xiong⁸ , Lan Hua⁹ , Yefeng Tang^1,* , Gelin Wang^1,*

¹School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China
²Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Peking University, Beijing, China
³Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, Beijing, China
⁴Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, China
⁵Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China
⁶Neuroscience Research Institute, Peking University, Beijing, China
⁷Beijing Advanced Innovation Center for Intelligent Robots and System, Beijing Institute of Technology, Beijing, China
⁸School of Life Sciences, Tsinghua University, Beijing, China
⁹GHDDI, Beijing, China
^†These authors contributing equally: Hong Yao, Minghui Liu, Leibo Wang, Yumeng Zu, Chou Wu
Correspondence: Yefeng Tang(yefengtang@tsinghua.edu.cn)Gelin Wang(gelinwang@tsinghua.edu.cn)

The decline of nicotinamide adenine dinucleotide (NAD) occurs in a variety of human pathologies including neurodegeneration. NAD-boosting agents can provide neuroprotective benefits. Here, we report the discovery and development of a class of potent activators (NATs) of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway. We obtained the crystal structure of NAMPT in complex with the NAT, which defined the allosteric action of NAT near the enzyme active site. The optimization of NAT further revealed the critical role of K189 residue in boosting NAMPT activity. NATs effectively increased intracellular levels of NAD and induced subsequent metabolic and transcriptional reprogramming. Importantly, NATs exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any overt toxicity. These findings demonstrate the potential of NATs in the treatment of neurodegenerative diseases or conditions associated with NAD level decline.

https://doi.org/10.1038/s41422-022-00651-9

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