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    Home > Active Ingredient News > Study of Nervous System > 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

    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

    • Last Update: 2022-06-08
    • Source: Internet
    • Author: User
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    Decreases in iNature nicotinamide adenine dinucleotide (NAD) occur in a variety of human diseases including neurodegeneration

    .

    NAD enhancers may provide neuroprotection
    .

    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

    .

    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
    .

    Optimization of NAT further revealed the critical role of the K189 residue in promoting NAMPT activity
    .

    NATs potently increased intracellular levels of NAD and induced subsequent metabolic and transcriptional reprogramming
    .

    Importantly, NATs exhibited robust neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any apparent toxicity
    .

    These findings demonstrate the potential of NAT in the treatment of neurodegenerative diseases or conditions associated with decreased NAD levels
    .

    Nicotinamide adenine dinucleotide (NAD) is a widely distributed metabolite with important cellular functions
    .

    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
    .

    This flow of electrons occurs in many metabolic pathways, especially driving energy production
    .

    For example, NAD accepts electrons to produce NADH during glycolysis or the TCA cycle
    .

    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
    .

     NAD also acts as a non-redox cofactor or substrate for some NAD-dependent enzymes that regulate various cellular processes
    .

    Therefore, strict maintenance of NAD homeostasis is critical for proper cellular function
    .

    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
    .

    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)
    .

    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)
    .

    NMNAT enzymes are involved in de novo NAD synthesis and recovery of NAD from nicotinamide
    .

    Therefore, NAMPT and NMNAT are essential for maintaining adequate intracellular NAD levels
    .

    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
    .

    Deletion of NAMPT or NMNAT in adult mouse neurons results in neurodegeneration and death
    .

    Targeting NAD metabolism can improve neuronal cell health, memory, and cognitive function in animal models of disease
    .

    To this end, supplementation of NAD precursors, enhancement of NAD biosynthesis, and inhibition of NAD depletion have been used
    .

    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
    .

    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
    .

    This study defines the structural basis for the activation and regulation of NAMPT by NAT chemicals
    .

    This work lays the foundation for the development of new therapeutics against neurodegenerative diseases
    .

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