NMN/NaMN Adenylyltransferase (NMNAT) and NAD Kinase (NADK) Inhibitors: Chemistry and Potential Therapeutic Applications

R.      Petrelli; K.      Felczak; L.      Cappellacci

Abstract

Nicotinamide adenine dinucleotide (NAD+) has a crucial role in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Thus, enzymes involved in NAD+ metabolism are attractive targets for drug discovery against a variety of human diseases. Herein we focus on two of them: NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK). NMNAT is a key enzyme in all organisms catalyzing coupling of ATP and NMN or NaMN yielding NAD or NaAD, respectively. NADKs are ubiquitous enzymes involved in the last step of the biosynthesis of NADP. They phosphorylate NAD to produce NADP using ATP (or inorganic polyphosphates) in the presence of Mg2+. No other pathway of NADP biosynthesis has been found in prokaryotic or eukaryotic cells. In this review we provide a comprehensive summary of NMNAT and NADK inhibitors highlighting their chemical modifications by different synthetic approaches, and structure-activity relationships depending on their potential therapeutic applications

Keywords: NAD(P) biosynthesis, NAD-based therapeutics, NAD analogues, NMNAT, NadD, NAD kinase, inhibitor design, Nicotinamide adenine dinucleotide, adenylyltransferase, catalyzing coupling