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Publication Abstract from PubMed

Evidence supports boosting nicotinamide adenine dinucleotide (NAD(+)) to counteract oxidative stress in aging and neurodegenerative disease. One approach is to enhance the activity of nicotinamide phosphoribosyltransferase (NAMPT). Novel NAMPT positive allosteric modulators (N-PAMs) were identified. A cocrystal structure confirmed N-PAM binding to the NAMPT rear channel. Early hit-to-lead efforts led to a 1.88-fold maximum increase in the level of NAD(+) in human THP-1 cells. Select N-PAMs were assessed for mitigation of reactive oxygen species (ROS) in HT-22 neuronal cells subject to inflammatory stress using tumor necrosis factor alpha (TNFalpha). N-PAMs that increased NAD(+) more effectively in THP-1 cells attenuated TNFalpha-induced ROS more effectively in HT-22 cells. The most efficacious N-PAM completely attenuated ROS elevation in glutamate-stressed HT-22 cells, a model of neuronal excitotoxicity. This work demonstrates for the first time that N-PAMs are capable of mitigating elevated ROS in neurons stressed with TNFalpha and glutamate and provides support for further N-PAM optimization for treatment of neurodegenerative diseases.

Nicotinamide Phosphoribosyltransferase Positive Allosteric Modulators Attenuate Neuronal Oxidative Stress.,Gordon-Blake J, Ratia K, Weidig V, Velma GR, Ackerman-Berrier M, Penton C, Musku SR, Alves ETM, Driver T, Tai L, Thatcher GRJ ACS Med Chem Lett. 2024 Jan 24;15(2):205-214. doi: , 10.1021/acsmedchemlett.3c00391. eCollection 2024 Feb 8. PMID:38352833^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.