Nicotinamide Phosphoribosyltransferase Positive Allosteric Modulators Attenuate Neuronal Oxidative Stress

Jesse Gordon-Blake, Kiira Ratia, Victoria Weidig, Ganga Reddy Velma, Martha Ackerman-Berrier, Christopher Penton, Soumya Reddy Musku, Erick T.M. Alves, Tom Driver, Leon Tai, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 (TNFα). N-PAMs that increased NAD+ more effectively in THP-1 cells attenuated TNFα-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 TNFα and glutamate and provides support for further N-PAM optimization for treatment of neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)205-214
Number of pages10
JournalACS Medicinal Chemistry Letters
Issue number2
StatePublished - Feb 8 2024


  • Aging
  • Allosteric activation
  • NAD
  • Neuroinflammation
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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