2. Academic Validation
  3. Optimization of NAMPT activators to achieve in vivo neuroprotective efficacy

Optimization of NAMPT activators to achieve in vivo neuroprotective efficacy

  • Eur J Med Chem. 2022 Jun 5;236:114260. doi: 10.1016/j.ejmech.2022.114260.
Leibo Wang 1,  Minghui Liu 1,  Yumeng Zu 1,  Hong Yao 2,  Chou Wu 3,  Ruoxi Zhang 1,  Weinan Ma 1,  Haigen Lu 1,  Shuang Xi 1,  Yang Liu 1,  Lan Hua 4,  Gelin Wang 5,  Yefeng Tang 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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, Tsinghua University, Beijing, 100084, China.
  • 4 Global Health Drug Discovery Institute, Beijing, 100192, China.
  • 5 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. Electronic address: gelinwang@tsinghua.edu.cn.
  • 6 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. Electronic address: yefengtang@tsinghua.edu.cn.
PMID: 35385807 DOI: 10.1016/j.ejmech.2022.114260
Abstract

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.

Keywords

Activator; NAD; NAMPT; Neuroprotective agent.

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