Wang 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
School 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, 100084, China.
School 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, 100084, China; Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Peking University, Beijing, 100871, China.
Eur J Med Chem. 2022 Jun 5;236:114260. doi: 10.1016/j.ejmech.2022.114260. Epub 2022 Mar 16.
NAMPT 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.
烟酰胺磷酸核糖转移酶（NAMPT）是烟酰胺腺嘌呤二核苷酸（NAD）补救途径中的限速酶，这使其成为治疗许多与NAD耗竭相关疾病（如神经退行性疾病）的有吸引力的靶点。在此，我们基于NAMPT-NAT复合物的共晶体结构，展示了对NAT的系统优化，NAT是我们通过高通量筛选发现的NAMPT激活剂的初始命中物。已设计并合成了80多种NAT衍生物，其中化合物72作为NAMPT激活剂表现出显著提高的效力，并有效保护培养细胞免受FK866介导的毒性。此外，化合物72在化疗诱导的周围神经病变（CIPN）小鼠模型中表现出强大的神经保护功效，且无任何明显毒性，这使其成为开发新型神经保护剂的有希望的候选物。
