Scientists have deduced the mode of action for a powerful neuroprotective drug class and are now trying to develop a compound into a therapy. On September 11, collaborators from the University of Texas Southwestern Medical Center in Dallas, the University Iowa Carver College of Medicine, Iowa City, and Calico Life Sciences in Mountain View, California, announced that Calico will develop the class of compounds, known as P7C3. On the same day in the journal Cell, the UT researchers reported that P7C3s work by boosting synthesis of nicotinamide adenine dinucleotide (NAD), a crucial co-factor in a variety of metabolic pathways.
Steven McKnight and Joseph Ready of UT Southwestern developed the compounds along with co-author Andrew Pieper, who now works at the University of Iowa Carver College of Medicine in Iowa City. They first identified the parent chemical in a broad screen for drugs that would enhance neurogenesis in mice. This is how the molecule got its name: It was compound three in the seventh pool of chemicals Pieper tried (see Jul 2010 news story). From that initial three-ring compound, chemists in Ready’s group have derived several other active chemicals. They protect newly born neurons from apoptosis, and appear to do the same for older neurons as well. The compounds benefit mouse models of amyotrophic lateral sclerosis, Parkinson’s disease, and traumatic brain injury (see Oct 2012 news story; Yin et al., 2014).
Despite this evidence of P7C3’s positive effects, the researchers had a puzzle on their hands. “Of significant concern was the fact that we have been ignorant of the mechanism of action of the P7C3 class of neuroprotective chemicals,” wrote first authors Gelin Wang and Ting Han of UT Southwestern and colleagues in the Cell report. They identified the molecule’s target via crosslinking experiments. The compound, it turns out, binds the enzyme nicotinamide phosphoribosyltransferase. NAMPT catalyzes the rate-limiting step in the conversion of nicotinamide to NAD. Han and Wang observed that P7C3 compounds enhanced production of NAD in both in vitro and cell culture assays, leading them to conclude that P7C3 activates NAMPT.
The finding fits into the scientific literature on neuroprotection, where NAD synthesis was known to be beneficial. For example, axons in certain mutant mice undergo unusually slow degeneration due to a genetic triplication that boosts levels of another NAD synthesis enzyme, nicotinamide mononucleotide adenylyltransferase (NMN) (see Nov 2001 news story). Treatment with NAD alone protects axons from degeneration (see Aug 2004 news story). In addition, NAD acts as a coenzyme for another crucial player in neuroprotection and anti-aging research, the deacetylases known as sirtuins (see Jul 2008 news story).
The UT Southwestern researchers initially licensed P7C3 to 2M Companies of Dallas, a life science investment firm focused on early stage development. With the new announcement, Calico, which is tackling aging and age-related diseases, takes the helm to develop and commercialize the compounds. If P7C3 works in people, it could have broad applications even beyond the brain, suggest the Cell study authors. They note that treatment with P7C3 or NMN allows aging rodents to maintain cognitive ability and body weight (Gomes et al., 2013). Wang and Han speculate that P7C3 compounds might stave off some of the frailty associated with aging.
Wang G, Han T, Nijhawan D, Theodoropoulos P, Naidoo J, Yadavalli S, Mirzaei H, Pieper AA, Ready JM, McKnight SL. P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell. 2014 Sep 11;158(6):1324-34. PubMed.
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