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Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity
Cell Research ( IF 28.1 ) Pub Date : 2022-04-22 , DOI: 10.1038/s41422-022-00651-9
Hong Yao 1, 2 , Minghui Liu 1 , Leibo Wang 1 , Yumeng Zu 1 , Chou Wu 1, 3 , Chenyu Li 1 , Ruoxi Zhang 1 , Haigen Lu 4 , Feifei Li 1 , Shuang Xi 1 , Shuangquan Chen 1 , Xuanyu Gu 1 , Tianya Liu 5 , Jie Cai 6 , Shirong Wang 7 , Maojun Yang 5 , Guo-Gang Xing 6 , Wei Xiong 8 , Lan Hua 9 , Yefeng Tang 1 , Gelin Wang 1
Affiliation  

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.



中文翻译:

烟酰胺磷酸核糖转移酶 (NAMPT) 小分子激活剂的发现及其临床前神经保护活性

烟酰胺腺嘌呤二核苷酸 (NAD) 的下降发生在包括神经变性在内的多种人类病理学中。NAD 促进剂可以提供神经保护作用。在这里,我们报告了一类烟酰胺磷酸核糖基转移酶 (NAMPT) 的有效激活剂 (NAT) 的发现和开发,NAMPT 是 NAD 补救途径中的限速酶。我们获得了与 NAT 复合的 NAMPT 的晶体结构,它定义了 NAT 在酶活性位点附近的变构作用。NAT 的优化进一步揭示了 K189 残基在促进 NAMPT 活性中的关键作用。NAT 有效地增加了细胞内 NAD 的水平,并诱导了随后的代谢和转录重编程。重要的,NATs 在化疗引起的周围神经病变 (CIPN) 小鼠模型中表现出强烈的神经保护作用,没有任何明显的毒性。这些发现证明了 NAT 在治疗神经退行性疾病或与 NAD+ 水平下降相关的病症方面的潜力。

更新日期:2022-04-22
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