title: NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK) inhibitors: chemistry and potential therapeutic applications.
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 Mg(2+). 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.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Petrelli
authors.forename: K
authors.initials: K
authors.lastname: Felczak
authors.forename: L
authors.initials: L
authors.lastname: Cappellacci
mesh_terms: D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); C021844:NAD kinase; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C038480:nicotinic acid mononucleotide adenylyltransferase