The SIRT1 inhibitor, nicotinamide, inhibits hepatitis B virus replication in vitro and in vivo

Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.

Since the beginning of the last century, seminal discoveries have identified pyridine nucleotides as the major redox carriers in all organisms. Recent research has unravelled an unexpectedly wide array of signalling pathways that involve nicotinamide adenine dinucleotide (NAD) and its phosphorylated form, NADP. NAD serves as substrate for protein modification including protein deacetylation, and mono- and poly-ADP-ribosylation. Both NAD and NADP represent precursors of intracellular calcium-mobilizing molecules. It is now beyond doubt that NAD(P)-mediated signal transduction does not merely regulate metabolic pathways, but might hold a key position in the control of fundamental cellular processes. The comprehensive molecular characterization of NAD biosynthetic pathways over the past few years has further extended the understanding of the multiple roles of pyridine nucleotides in cell biology.

Infection with hepatitis B virus (HBV) may lead to acute or chronic hepatitis. HBV infections were previously much more frequent but there are still 240 million chronic HBV carriers today and ca. 620,000 die per year from the late sequelae liver cirrhosis or hepatocellular carcinoma. Hepatitis B was recognized as a disease in ancient times, but its etiologic agent was only recently identified. The first clue in unraveling this mystery was the discovery of an enigmatic serum protein named Australia antigen 50 years ago by Baruch Blumberg. Some years later this was recognized to be the HBV surface antigen (HBsAg). Detection of HBsAg allowed for the first time screening of inapparently infected blood donors for a dangerous pathogen. The need to diagnose clinically silent HBV infections was a strong driving force in the development of modern virus diagnostics. HBsAg was the first infection marker to be assayed with a highly sensitive radio immune assay. HBV itself was among the first viruses to be detected by assay of its DNA genome and IgM antibodies against the HBV core antigen were the first to be selectively detected by the anti-μ capture assay. The cloning and sequencing of the HBV genome in 1978 paved the way to understand the viral life cycle, and allowed development of efficient vaccines and drugs. Today’s hepatitis B vaccine was the first vaccine produced by gene technology. Among the problems that still remain today are the inability to achieve a complete cure of chronic HBV infections, the recognition of occult HBV infections, their potential reactivation and the incomplete protection against escape mutants and heterologous HBV genotypes by HBV vaccines.