Nicotinamide Adenine Dinucleotide Based Therapeutics

K.   W.   Pankiewicz; L.      Chen; R.      Petrelli; K.      Felczak; G.      Gao; L.      Bonnac; J.   S.   Yu; E.   M.   Bennett

Abstract

Nicotinamide adenine dinucleotide (NAD), generally considered a key component involved in redox reactions, has been found to participate in an increasingly diverse range of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. In recent years, medicinal chemists have become interested in the therapeutic potential of molecules affecting interactions of NAD with NAD-dependent enzymes. Also, enzymes involved in de novo biosynthesis, salvage pathways, and down-stream utilization of NAD have been extensively investigated and implicated in a wide variety of diseases. These studies have bolstered NAD-based therapeutics as a new avenue for the discovery and development of novel treatments for medical conditions ranging from cancer to aging. Industrial and academic groups have produced structurally diverse molecules which target NAD metabolic pathways, with some candidates advancing into clinical trials. However, further intensive structural, biological, and medical studies are needed to facilitate the design and evaluation of new generations of NAD-based therapeutics. At this time, the field of NAD-therapeutics is most likely at a stage similar to that of the early successful development of protein kinase inhibitors, where analogs of ATP (a more widely utilized metabolite than NAD) began to show selectivity against target enzymes. This review focuses on key representative opportunities for research in this area, which extends beyond the scope of this article.

Keywords: NAD analogues, IMPDH, histone deacetylases, PARP, NMNAT, NAD kinase, inhibitor design

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