Channeling NAMPT Ligands To Address Life and Death

Abstract

Aging and age-related diseases are often associated with the breakdown of our metabolic system. NAD-metabolism maintains homeostasis by tightly regulating NAD+ and its metabolites. As we age, NAD+ levels in our cells drop which leads to metabolic disruption. Cancers alter NAD+ metabolism of cells, either becoming addicted to the Preiss-handler or salvage pathway. NAMPT plays a central role in regulating NAD+ in healthy, aging, and cancerous cells. In this work, several series of NAMPT ligands were developed and tested for their NAMPT activity and regulation of NAD+ in vitro and in vivo. Several series of NAMPT activators were shown to increase NAD+ and ultimately increase cell viability. The mechanism of activation of N-PAMs incorporates both reduced substrate inhibition of NAM and reduced degradation of ATP. One series showed promising BBB penetration to target aging diseases of the brain. Additionally, studies were conducted to investigate the unique toxicity of Vacor, a NAMPT inhibitor and substrate. Analogues of Vacor were able to replicate potent cell toxicity and form PR-adducts through the NAMPT-mediated reaction with PRPP. NAMPT activators would have therapeutic utility in diseases which NAD+ precursor supplementation (NR, NMN, NA, NAM) has shown some efficacy, as these activators would increase NAD+ biosynthesis by blocking feedback inhibition. Substrate inhibitors would have toxicity in cancers which are NAMPT addicted and/or NAPRT silenced. Vacor and analogues toxicity is likely due to inhibition of both NAMPT and NMNAT leading to cell death by conversion to toxic NMN and NAD+ analogues which disrupt NAD-metabolism.