Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) has crucial roles in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Enzymes involved in NAD⁺ metabolism are attractive targets for drug discovery against a variety of human diseases, including cancer, multiple sclerosis, neurodegeneration and Huntington’s disease. A small-molecule inhibitor of nicotinamide phosphoribosyltransferase, an enzyme in the salvage pathway of NAD⁺ biosynthesis, is presently in clinical trials against cancer. An analog of a kynurenine pathway intermediate is efficacious against multiple sclerosis in an animal model. Indoleamine 2,3-dioxygenase plays an important role in immune evasion by cancer cells and other disease processes. Inhibitors against kynurenine 3-hydroxylase can reduce the production of neurotoxic metabolites while increasing the production of neuroprotective compounds. This review summarizes the existing knowledge on NAD⁺ metabolic enzymes, with emphasis on their relevance for drug discovery.

Keywords::

• ADP-ribosylation
• calcium signaling
• FK866
• indoleamine 2,3-dioxygenase
• inosine mononucleotide dehydrogenase
• kynurenines
• multiple sclerosis
• nicotinamide phosphoribosyltransferase
• pre-B-cell colony-enhancing factor
• protein deacetylation
• sirtuins
• tiazofurin

Acknowledgements

This work was supported in part by a R01 grant (DK67238) from the NIH to L Tong and a grant (P50 GM62413) from the Protein Structure Initiative from the NIH.