[PDF][PDF] P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage

G Wang, T Han, D Nijhawan, P Theodoropoulos… - Cell, 2014 - cell.com
G Wang, T Han, D Nijhawan, P Theodoropoulos, J Naidoo, S Yadavalli, H Mirzaei…
Cell, 2014cell.com
The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a
variety of rodent models of neurodegeneration or nerve cell injury. To uncover its
mechanism of action, an active derivative of P7C3 was modified to contain both a
benzophenone for photocrosslinking and an alkyne for CLICK chemistry. This derivative was
found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme
involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD) …
Summary
The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photocrosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.
cell.com