| Title | Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity |
| Authors | Yao, Hong Liu, Minghui Wang, Leibo Zu, Yumeng Wu, Chou Li, Chenyu Zhang, Ruoxi Lu, Haigen Li, Feifei Xi, Shuang Chen, Shuangquan Gu, Xuanyu Liu, Tianya Cai, Jie Wang, Shirong Yang, Maojun Xing, Guo-Gang Xiong, Wei Hua, Lan Tang, Yefeng Wang, Gelin |
| Affiliation | Tsinghua Univ, Key Lab Bioorgan Phosphorus Chem & Chem Biol, Sch Pharmaceut Sci, Beijing Adv Innovat Ctr Struct Biol,Minist Educ, Beijing, Peoples R China Peking Univ, Sch Life Sci, Joint Grad Program Peking Tsinghua NIBS, Beijing, Peoples R China Tsinghua Univ, Sch Life Sci, Joint Grad Program Peking Tsinghua NIBS, Beijing, Peoples R China Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Beijing, Peoples R China Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Beijing Adv Innovat Ctr Struct Biol, Minist Educ,Key Lab Prot Sci,Sch Life Sci, Beijing, Peoples R China Peking Univ, Neurosci Res Inst, Beijing, Peoples R China Beijing Inst Technol, Beijing Adv Innovat Ctr Intelligent Robots & Syst, Beijing, Peoples R China Tsinghua Univ, Sch Life Sci, Beijing, Peoples R China GHDDI, Beijing, Peoples R China |
| Keywords | NAD(+) METABOLISM ENERGY HOMEOSTASIS MOUSE MODEL SARM1 CELLS BIOSYNTHESIS DELETION INHIBITION MECHANISM NEURONS |
| Issue Date | Apr-2022 |
| Publisher | CELL RESEARCH |
| Abstract | 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. |
| URI | http://hdl.handle.net/20.500.11897/642554 |
| ISSN | 1001-0602 |
| DOI | 10.1038/s41422-022-00651-9 |
| Indexed | SCI(E) |
| Appears in Collections: | 生命科学学院 医学部待认领 |
