Editorial [Hot Topic: NAD and its Role in Biology and Medicine (Guest Editor: Krzysztof W. Pankiewicz)]
Abstract:This special issue of Current Medicinal Chemistry focuses on the chemistry and biology of nicotinamide adenine dinucleotide (NAD and NADP). In recent years, NAD(P)-utilizing enzymes have been extensively investigated and implicated in a wide variety of diseases. Thus, understanding of the role of NAD(P) in medical disorders may lead to potential NAD(P)-based therapeutics.
NAD(P) is not only a key component of redox reactions but also participates in a diverse range of cellular processes that are crucial for the cell health and replication. There is a growing interest in identification of small molecules as modulators of NAD(P)-dependent enzymes implicated in a variety of diseases.
In the first chapter, Felczak and Pankiewicz reviewed a number of conformational and structural factors that might affect (improve) the affinity of various inhibitors to the NAD-binding domain. They discussed potential selectivity of NAD(P)-like molecules toward human IMPdehydrogenase (IMPDH) and other target enzymes, which is crucial for potential application of NAD analogues as therapeutic agents.
Hedstrom at al. focused on bacterial IMPDHs as potential target for the development of new antibiotics. These enzymes share only 20-40% of amino acids sequences with the human enzyme. The identification of the structural features in IMPDHs from a wide variety of pathogenic bacteria is described as well as the discovery of an inhibitor against Helicobacter pylori.
Sauve and co-workers reviewed biochemical activities of seven human sirtuin isoforms called SIRT1-7 and their roles in biology. These enzymes are involved in post-translational protein modifications, including NAD-dependent histone deacetylation. Strategies for how sirtuins can be targeted by small molecules are discussed.
Chen described early sirtuin inhibitors that mimic NAD+ or substrate peptides as well as new structures identified by high-throughput and in silico screenings. His review outlines inhibitor chemotypes, and their biological evaluations, highlighting strategies to enhance inhibition, and selectivity among isoforms.
Burgos reviewed the role of nicotinamide phosphoribosyltransferase (NAMPT), the enzyme which catalyzes the first step in the salvage pathway of NAD biosynthesis. The first NAMPT inhibitors entered clinical trials; however, it is clear that better understanding of the catalytic mechanism of NAMPT may permit the design of improved NAMPT inhibitors as potential drugs against cancer.
Jayaram and co-workers focused on nicotinamide mononucleotide adenylyltransferease (NMNAT), an enzyme present in all organisms and involved in the biosynthesis of NAD from ATP and nicotinamide mononucleotide (NMN). The role of NMNAT in the regulation of NAD levels in the cell and consequently the enzyme effects on performance of NAD-utilizing enzymes are discussed.
Cappellacci at al. described the design, chemistry, and potential therapeutic applications of inhibitors of the two last enzymes in NAD and NADP biosynthesis, i.e. NMNAT and NAD kinase. They concluded that the recognized role of NADKs and NMNATs in pathological conditions like cancer, and neuro-degenerative diseases makes these enzymes excellent targets for drug discovery. Also, bacterial NADK and NaMNAT are promising new targets for developing novel antibiotics.
Finally, all chapters indicate enormous potential for innovative research in this field. NAD-based therapeutics are still in the early stage of development but the NAD-related field progresses faster than ever before.
Document Type: Research Article
Publication date: May 1, 2011
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- Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.