Cell Res Tsinghua University Wang Gelin/Tang Yefeng developed a small molecule activator of nicotinamide phosphoribosyltransferase, laying the foundation for the development of new anti-neurodegenerative disease therapeutics

Decreases in iNature nicotinamide adenine dinucleotide (NAD) occur in a variety of human diseases including neurodegeneration
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NAD enhancers may provide neuroprotection
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On April 22, 2022, Tsinghua University Wang Gelin and Tang Yefeng jointly published a research paper entitled "Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity" in Cell Research online.
Discovery and development of potent activators (NATs) of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD salvage pathway
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This study obtained the crystal structure of NAMPT in complex with NAT, which defines the allosteric role of NAT near the active site of the enzyme
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Optimization of NAT further revealed the critical role of the K189 residue in promoting NAMPT activity
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NATs potently increased intracellular levels of NAD and induced subsequent metabolic and transcriptional reprogramming
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Importantly, NATs exhibited robust neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any apparent toxicity
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These findings demonstrate the potential of NAT in the treatment of neurodegenerative diseases or conditions associated with decreased NAD levels
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Nicotinamide adenine dinucleotide (NAD) is a widely distributed metabolite with important cellular functions
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NAD acts as a coenzyme for hundreds of dehydrogenases in redox reactions, where hydride is transferred from the substrate to the oxidized form of NAD (NAD+) to form the reduced form of NADH, a universal electron carrier
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This flow of electrons occurs in many metabolic pathways, especially driving energy production
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For example, NAD accepts electrons to produce NADH during glycolysis or the TCA cycle
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NADH formed by these catabolic pathways brings electrons to the first step of the electron transport chain in mitochondria, thereby initiating a proton pump across the membrane to generate ATP through oxidative phosphorylation
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 NAD also acts as a non-redox cofactor or substrate for some NAD-dependent enzymes that regulate various cellular processes
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Therefore, strict maintenance of NAD homeostasis is critical for proper cellular function
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Decrease in cellular or tissue NAD levels is associated with aging and the pathophysiology of various human diseases or disorders, such as neurodegeneration, metabolic syndrome, and cancer
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NAD can be synthesized de novo from tryptophan via the kynurenine pathway, as well as via the salvage pathway of nicotinamide (NAM) and the Preiss-Handler pathway of niacin (NA)
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Among these pathways, mammals rely primarily on the recovery of NAD from NAM, where the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the condensation of NAM and phosphoribosyl pyrophosphate (PRPP) to nicotinamide mononucleotide (NMN) ), and then NAD is generated by nicotinamide mononucleotide adenylyltransferase (NMNAT)
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NMNAT enzymes are involved in de novo NAD synthesis and recovery of NAD from nicotinamide
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Therefore, NAMPT and NMNAT are essential for maintaining adequate intracellular NAD levels
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NAT binds to and directly activates NAMPT (image from Cell Research) The discovery and development of drugs for neurodegenerative diseases is notoriously challenging with extremely low success rates
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Deletion of NAMPT or NMNAT in adult mouse neurons results in neurodegeneration and death
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Targeting NAD metabolism can improve neuronal cell health, memory, and cognitive function in animal models of disease
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To this end, supplementation of NAD precursors, enhancement of NAD biosynthesis, and inhibition of NAD depletion have been used
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In this context, small-molecule NAMPT activators may hold promise to transform the treatment of a wide range of neuronal diseases associated with impaired NAD production
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Here, we report the discovery of a chemical-like NAMPT activator (NAT) that promotes neural stem cell proliferation in vitro and exhibits neuroprotection in a preclinical mouse model of chemotherapy-induced peripheral neuropathy (CIPN) efficacy
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This study defines the structural basis for the activation and regulation of NAMPT by NAT chemicals
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This work lays the foundation for the development of new therapeutics against neurodegenerative diseases
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