TitleDiscovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity
AuthorsYao, 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
AffiliationTsinghua 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
KeywordsNAD(+) METABOLISM
ENERGY HOMEOSTASIS
MOUSE MODEL
SARM1
CELLS
BIOSYNTHESIS
DELETION
INHIBITION
MECHANISM
NEURONS
Issue DateApr-2022
PublisherCELL RESEARCH
AbstractThe 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.
URIhttp://hdl.handle.net/20.500.11897/642554
ISSN1001-0602
DOI10.1038/s41422-022-00651-9
IndexedSCI(E)
Appears in Collections:生命科学学院
医学部待认领

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