Boosting NAD+ with a small molecule that activates NAMPT

Gardell, Stephen J.; Hopf, Meghan; Khan, Adnan Ahmad; Dispagna, Mauro; Sessions, E. Hampton; Falter, Rebecca; Kapoor, Nidhi; Brooks, Jeanne Kaye; Culver, Jeffrey A.; Petucci, Chris; Chen, Ting; Cohen, Steven E.; Tanaka, Jun; Burgos, Emmanuel S.; Hirschi, Jennifer S.; Smith, Steven R.; Sergienko, Eduard; Pinkerton, Anthony B.

doi:10.1038/s41467-019-11078-z

Cited by 124 publications

(137 citation statements)

References 31 publications

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“…635,637,638 SBI-797812 activates NAMPT via stabilizing the NAMPT phosphorylation at His247, enhancing the efficiency of NMN generation, providing another option to raise NAD + . 639 Together, the NAMPT enhancers, P7C3 and SBI-797812, warrant further study for the clinical treatment of neuron related diseases.…”

Section: Inhibition Of Nad + Consumptionmentioning

confidence: 99%

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Xie

Zhang

Gao

et al. 2020

Sig Transduct Target Ther

551

383

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Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

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Section: Inhibition Of Nad + Consumptionmentioning

confidence: 99%

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Xie

Zhang

Gao

et al. 2020

Sig Transduct Target Ther

551

383

View full text Add to dashboard Cite

show abstract

“…3A). We next determined if the PARP10-mediated loss in NAD + could be restored by increasing cytosolic NAD + synthesis with SBI, a small molecule activator of NAMPT, which promotes NAM salvage (23). SBI enhanced NAD + synthesis in GFP expressing cells, but did not significantly enhance NAD + in PARP10 expressing cells, indicating that PARP10 expression is sufficient to limit cellular NAD + (Fig.…”

Section: Parp10 Overexpression Is Sufficient To Depress Nad + Levelsmentioning

confidence: 99%

“…Here we show that PARP10 overexpression is sufficient to depress cellular NAD + and that the MARylating activities of PARP10, PARP12 and PARP14 can be pharmacologically increased by enhancing NAD salvage synthesis (salvage?) with SBI-797812 (SBI), a NAMPT activator (23).…”

mentioning

confidence: 99%

Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity

Heer

Sanderson²,

Voth

et al. 2020

Preprint

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ABSTRACTInnate immune responses are critical to control of viruses. Coronaviruses (CoVs) are positive strand RNA viruses with double-stranded RNA replication intermediates that are recognized by the innate immune system. Upon recognition, infected cells secrete interferon, which induces a set of interferon-stimulated genes that inhibit viral replication. Here we show that SARS-CoV-2 infection strikingly dysregulates the set of genes involved in consumption and biosynthesis of nicotinamide adenine dinucleotide (NAD). Highly induced genes include those encoding noncanonical poly(ADP-ribose) polymerase (PARP) family members known to function as mono ADP-ribosyltransferases but not known to deplete cellular NAD and genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR). We demonstrate that overexpression of PARP10 is sufficient to depress NAD levels and that the enzymatic activities of PARP10, PARP12 and PARP14 are limited by and can be enhanced by pharmacological activation of NAM salvage. We further showed that infection with the β-coronavirus murine hepatitis virus (MHV) induces a severe attack on host cell NAD+ and NADP+. Finally we show that NAMPT activation, NAM and NR dramatically decrease replication in a MHV infection model that is sensitive to PARP activity. The data show that the antiviral activities of noncanonical PARP isozyme activities are limited by their own consumption of cellular NAD and that nutritional and pharmacological interventions to enhance NAD-based defenses may boost innate immunity.

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“…Different studies identified small molecules able to enhance NAMPT expression, such as P7C3, and ultimately NAD + cellular content [ 98 ]. More recently, SBI-797812 has been identified as a NAMPT activator, which increased levels of NAD + in the heart of treated mice [ 99 ].…”

Section: Clinical Perspectives Targeting Nad +mentioning

confidence: 99%

Need for NAD+: Focus on Striated Muscle Laminopathies

Cardoso

Muchir

2020

Cells

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Laminopathies are a heterogeneous group of rare diseases caused by genetic mutations in the LMNA gene, encoding A-type lamins. A-type lamins are nuclear envelope proteins which associate with B-type lamins to form the nuclear lamina, a meshwork underlying the inner nuclear envelope of differentiated cells. The laminopathies include lipodystrophies, progeroid phenotypes and striated muscle diseases. Research on striated muscle laminopathies in the recent years has provided novel perspectives on the role of the nuclear lamina and has shed light on the pathological consequences of altered nuclear lamina. The role of altered nicotinamide adenine dinucleotide (NAD+) in the physiopathology of striated muscle laminopathies has been recently highlighted. Here, we have summarized these findings and reviewed the current knowledge about NAD+ alteration in striated muscle laminopathies, providing potential therapeutic approaches.

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Boosting NAD+ with a small molecule that activates NAMPT

Cited by 124 publications

References 31 publications

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity

Need for NAD+: Focus on Striated Muscle Laminopathies

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