Recently, the team of Wang Gelin and Tang Yefeng from the School of Pharmacy, Tsinghua University, aimed at the major needs in the field of population and health, targeting NAD metabolism regulation and neurodegeneration and other aging-related diseases, a new scientific frontier hotspot, through high-throughput drug screening and target structure-based analysis.
Through rational drug design, novel small molecule activators (NATs) targeting NAD biosynthesis rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) have been obtained, laying the foundation for the development of innovative drugs for the treatment of neurodegenerative diseases
As the global population ages, progressive neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and other diseases and treatment-induced acute neurodegenerative diseases such as stroke The incidence of peripheral neuropathy, chemotherapy, and diabetes-induced peripheral neuropathy is on the rise, becoming one of the main types of aging-related diseases
Current drugs can alleviate some symptoms, but effective drugs and treatment methods are lacking.
If any drug can safely and effectively prevent the degeneration and death of nerve cells, it will have great therapeutic significance and application prospects
Nicotinamide adenine dinucleotide (NAD) is an important metabolite widely distributed in animals and plants.
It has two main functions: one is as a redox carrier to participate in energy metabolism and other metabolic processes in the body; the other is as a series of NAD consumption Substrates of enzymes through which various signal transduction processes are regulated
The body must maintain adequate and constant levels of NAD through the very dynamic process of NAD metabolism to function properly
In recent years, increasing evidence has shown that NAD metabolism is at the regulatory center of neurodegeneration, and the maintenance of its homeostasis is critical for neurological health
In animal models of neurodegenerative diseases, increasing NAD levels can improve nerve cell health, memory, and cognitive function
At present, the most common way to increase NAD levels is to supplement NAD precursors, such as NR, NMN, NAM or NA.
There are several relevant clinical trials underway internationally, and NMN and NR have been used as anti-aging health care products or foods.
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Different from this, in this study, the research team of Wang Gelin and Tang Yefeng has taken a different approach, starting with the development of activators of key enzymes of NAD synthesis, and by enhancing the biosynthesis of NAD in vivo, to achieve the purpose of combating neurodegeneration
The study targets the key rate-limiting enzyme NAMPT in the salvage pathway of NAD biosynthesis
Compared with enzyme inhibitors, the discovery of enzyme activators is extremely challenging, so there are only a handful of known enzyme activators
In this study, Gelin Wang's group first discovered the NAMPT small molecule activator NAT through high-throughput screening, and further studied the mechanism of action and cytoprotective function of NAT (Figure 1)
For the first time, the researchers solved the crystal structure of NAMPT and the small molecule activator, and observed at the atomic level that the activator NAT acts on the inside of the catalytic pocket of NAMPT, and promotes the two substrates NAM by interacting with the region near the active site of the enzyme.
Condensation with PRPP to form NMN, enhancing the catalytic effect of NAMPT, thus showing allosteric activation of the enzyme
On this basis, Tang Yefeng's research group adopted the rational drug design concept, combined with the target and small molecule complex crystal structure information, systematically modified and optimized NAT (Figure 3), and finally obtained candidate drug molecules with significantly improved activity NAT-5r
Recently, the research team also published a research paper in "European Medicinal Chemistry", which reported in detail the structure optimization process and structure-activity relationship study of NAT, a small molecule activator of NAMPT, and further revealed the key molecules of such small molecules on NAMPT activation.
Studies have shown that NATs enhance intracellular NAD synthesis and induce metabolic and transcriptional reprogramming
Importantly, NATs exhibited favorable neuroprotective effects in an animal model of chemotherapy-induced peripheral neuropathy (Fig.
Compared with NAD precursors, NATs have the following advantages: 1.
It can effectively increase the intracellular NAD content; 2.
It has better bioavailability; 3.
It has a larger structure space for optimization of drug properties, simple synthesis and low cost 4.
The effect of NAMPT activators is also regulated at the rate-limiting step to meet the needs of cells under different physiological conditions
In conclusion, this research work provides a new perspective for understanding the occurrence and development of neurodegenerative diseases, and theoretically provides a proof-of-concept that NAD metabolites play an important role in neuroprotection, thereby providing a new basis for the development of drugs for neurodegenerative diseases.
Potential candidate targets and drugs are provided
Figure 1: Discovery of a novel NAMPT small molecule activator NAT by high-throughput screening
Figure 2: The mode of action between small molecules and targets revealed by the crystal structure of NAT and NAMPT complexes
Figure 3: Structural modification and optimization of the lead compound NAT
Figure 4: Neuroprotective effects of NAT and NAT-5r in a mouse model of CIPN
The above studies were published in Cell Research (CR) and European Journal of Medicinal Chemistry (EJMC) with the titles of "Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity" and "Optimization of NAMPT Activators" successively.
to Achieve in vivo Neuroprotective Efficacy" two research papers
Researcher Wang Gelin and Tang Yefeng are the co-corresponding authors of the CR paper, doctoral students Yao Hong, Liu Minghui, Wang Leibo, Zu Yumeng and Wu Chou are the co-first authors, and laboratory members Li Chenyu, Zhang Ruoxi, Lu Haigen, Li Feifei, Xi Shuang, Chen Shuangquan, Gu Xuanyu ; Researcher Xiong Wei, Professor Yang Maojun, and Dr.
Liu Tianya of Tsinghua University; Professor Xing Guogang and Dr.
Cai Jie of Peking University; Researcher Wang Shirong of Beijing Institute of Technology; Metabolism and lipidomics platform, cell imaging platform; assistance from researcher Cai Tao, sequencing platform of Beijing Institute of Life Sciences
This work was supported by the National Natural Science Foundation of China, the Tsinghua-Peking University Life Science Joint Center, the Tsinghua University Center for Advanced Structural Biology, and the Tsinghua University-Toyota Joint Research Fund
Researcher Tang Yefeng and Wang Gelin are the co-corresponding authors of the EJMC paper, doctoral candidates Wang Leibo, Liu Minghui, and Zu Yumeng are the co-first authors, and laboratory members Yao Hong, Wu Chou, Zhang Ruoxi, Ma Weinan, Lu Haigen, Xi Shuang, Liu Yang; GHDDI Hualan Dr.
is a co-author
This work was supported by the National Natural Science Foundation of China, the Beijing Natural Science Foundation, the Tsinghua-Peking University Life Science Joint Center, the Tsinghua University Advanced Structural Biology Center, and the Tsinghua University-Toyota Joint Research Fund