TitleOptimization of NAMPT activators to achieve in vivo neuroprotective efficacy
AuthorsWang, Leibo
Liu, Minghui
Zu, Yumeng
Yao, Hong
Wu, Chou
Zhang, Ruoxi
Ma, Weinan
Lu, Haigen
Xi, Shuang
Liu, Yang
Hua, Lan
Wang, Gelin
Tang, Yefeng
AffiliationTsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Sch Pharmaceut Sci, Minist Educ,Key Lab Bioorgan Phosphorus Chem & Ch, Beijing 100084, Peoples R China
Peking Univ, Sch Life Sci, Joint Grad Program Peking Tsinghua NIBS, Beijing 100871, Peoples R China
Tsinghua Univ, Sch Life Sci, Joint Grad Program Peking Tsinghua NIBS, Beijing 100084, Peoples R China
Global Hlth Drug Discovery Inst, Beijing 100192, Peoples R China
KeywordsNICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE
NAD(+) METABOLISM
PROTEIN SIR2
(-)-P7C3-S243
INHIBITOR
MECHANISM
DISCOVERY
Issue Date5-Jun-2022
PublisherEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
AbstractNAMPT is the rate-limiting enzyme in the NAD salvage pathway, which makes it an attractive target for the treatment of many diseases associated with NAD exhaustion such as neurodegenerative diseases. Herein, we present the systematic optimization of NAT, an initial hit of NAMPT activator discovered by us through high-throughput screening, based on the co-crystal structure of the NAMPT-NAT complex. Over 80 NAT derivatives have been designed and synthesized, among which compound 72 showed notably improved potency as NAMPT activator and effectively protected cultured cells from FK866-mediated toxicity. Moreover, compound 72 exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any overt toxicity, which renders it a promising candidate for the development of novel neuroprotective agents. (c) 2022 Elsevier Masson SAS. All rights reserved.
URIhttp://hdl.handle.net/20.500.11897/670156
ISSN0223-5234
DOI10.1016/j.ejmech.2022.114260
IndexedSCI(E)
Appears in Collections:生命科学学院

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