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P7C3 Neuroprotective Chemicals Function by Activating the Rate-Limiting Enzyme in NAD Salvage

P7C3 Neuroprotective Chemicals Function by Activating the Rate-Limiting Enzyme in NAD Salvage

Gelin Wang, Ting Han, Deepak Nijhawan, Pano Theodoropoulos, Jacinth Naidoo, Sivaramakrishnan Yadavalli, Hamid Mirzaei, Andrew A Pieper, Joseph M Ready, Steven L McKnight

Cell. 2014 Sep 11;158(6):1324-1334.

PMID: 25215490

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP301353968	P7C3		301353-96-8	Price

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