Current Drug Targets - Volume 14, Issue 6, 2013

The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health problem in industrialized countries, and new therapeutic strategies to prevent T2DM are urgently needed worldwide. It is well known that calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents and delay the onset of numerous age-related diseases, including diabetes. Molecules that mimic CR metabolically may therefore represent new therapeutic targets for T2DM. Sirtuin1 (SIRT1), the mammalian homolog of Sir2, was originally identified as a NAD+-dependent histone deacetylase, and its activity is closely associated with longevity under CR. Growing evidence suggests that SIRT1 regulates glucose-lipid metabolism through its deacetylase activity for many known substrates and has many roles in the metabolic pathway through its direct or indirect involvement in insulin signaling in insulin-sensitive organs, including adipose tissue, liver and skeletal muscle. In addition, SIRT1 regulates insulin secretion, and adiponectin production, inflammation, gluconeogenesis, circadian rhythms and oxidative stress, which together contribute to the development of insulin resistance. Moreover, the overexpression of SIRT1 and several SIRT1 activators have beneficial effects on glucose homeostasis and insulin sensitivity in diabetic animal models and humans. Therefore, SIRT1 may represent a new therapeutic target for the prevention of diseases related to insulin resistance and T2DM. In addition, SIRT3 and SIRT6 play crucial roles in glucose and lipid metabolism. In this review, we summarize the current understanding of the biological functions of SIRT1, SIRT3 and SIRT6 in metabolism and discuss their potential role as therapeutic targets in T2DM.

Nicotinamide adenine dinucleotide (NAD+) biosynthesis from nicotinamide is used by mammalian cells to replenish their NAD+ stores and to avoid unwanted nicotinamide accumulation. Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme in this biosynthetic pathway, almost invariably leads to intracellular NAD+ depletion and, when protracted, to ATP shortage and cell demise. Cancer cells and activated immune cells express high levels of NAMPT and are highly susceptible to NAMPT inhibitors, as shown by the activity of these agents in models of malignant and inflammatory disorders. As the spectrum of conditions which could benefit from pharmacological NAMPT inhibition becomes broader, the mechanisms accounting for their activity are also eventually becoming apparent, including the induction of autophagy and the impairment of Ca2+- and NF-κB-dependent signaling. Here, we discuss the rationales for exploiting NAMPT inhibitors in cancer and inflammatory diseases and provide an overview of the preclinical and clinical studies in which these agents have been evaluated.

Age-related diseases pose as an enormous problem on aging populations of the world. Despite the fact that many advances have been made on understanding of the neurodegeneration, there is still no cure available for the agerelated brain disorders. Sirtuins are NAD-dependent protein deacetylases that were shown to have beneficial effects against age-related diseases. SIRT1 and SIRT2 have been studied mostly in terms of neurodegenerative diseases and seem to have opposite effects. According to the recent findings, activators of SIRT1 and inhibitors of SIRT2 would benefit the brain from neurodegeneration. Despite the enormous amount of research that has been conducted so far, there is still no cure or treatment for almost all of the neurodegenerative disorders. In addition, the mechanisms underlying brain aging and also the link between aging and neurodegeneration are not understood. This review focuses on the role of sirtuins as possible drug targets for neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's Diseases.

Sirtuins are a family of NAD+-dependent protein deacetylases, which regulate cell survival and energy metabolism, inflammation and cancer. Recent studies have shown that sirtuin-1 (SIRT1) modulates Human Immunodeficiency Virus (HIV)-1 transcription. The HIV-1 Tat protein is a substrate for the deacetylase activity of SIRT1; SIRT1 recycles Tat to its unacetylated form, catalyzing a fundamental step to start new cycles of viral transcription. Moreover, Tat has been reported to promote T-cell hyperactivation by suppressing SIRT1 activity. In fact, Tat blocks the ability of SIRT1 to deacetylate lysine 310 in the p65 subunit of nuclear factor-κB (NF-κB) by interacting with the deacetylase domain of SIRT1. This mechanism leads therefore to the hyperactivation of NF-κB proinflammatory pathway and may likely contribute to the chronic immune activation state of HIV-infected individuals. In the present review we first briefly describe the biological functions of sirtuins, then we delineate the interplay between SIRT1 and HIV-1 and discuss the potential role of SIRT1 as a pharmacological target of HIV-1 replication.

Sir2-like proteins (Sirtuins) are a class of enzymes conserved throughout the kingdoms of life. In fact, from Archaea to Mammals, these (class III) NAD+-dependent deacetylases catalyse the removal of the acetyl moiety from a substrate protein. Sirtuins show a conserved central catalytic domain with two more variable amino- and carboxy-terminal flanking regions. Amino acid comparison of these central conserved catalytic core sequences allows us to divide Sirtuins into five different classes (I, II, III, IV and U). These proteins differ in their subcellular localization (i.e. in Eukaryotes they can be found in the nucleus, cytoplasm or mitochondria). In humans there are seven Sirtuins (SIRT1-7) that are implicated in various physiological processes including aging and age-related disorders such as neoplasms, cardiovascular, metabolic and neurodegenerative diseases, and inflammation. Nowadays, the estimated life expectancy is definitely longer than in the past thus, we may consider all aging-related problems as having a strong social impact. Consequently, Sirtuins are emerging, particularly from a pharmacological point of view, as new and valuable drug targets.

Sirtuins form a large homology family of enzymes found almost ubiquitously in living organisms and involved in numerous biological processes. The human genome encodes for seven paralog sirtuins, identified as SIRT1 – 7. In this review the major structural features of the sirtuin catalytic domain are illustrated and the relevant sources of biological information indicated. The multiple sequence alignment deduced from the optimal structural superposition of four human sirtuins having known three-dimensional structure, to which the amino acid sequences of the remaining three have been subsequently aligned, is also analyzed. The structure of the neighbor-joining tree deduced from the multiple sequence alignment, summarizing the evolutionary relationship among the member of the homology family is illustrated also in relation with the distinct catalytic activities detected in members this homology family.

Silent information regulator 2 (Sir2) proteins, or sirtuins, are a family of proteins which influence several physiological responses and have implications for treating diseases of ageing. In this context, we have presented a summarized view on the discovery of Sir2 family proteins, the enzymatic activities, the role of sirtuins in aging, lifespan and onset of age-related symptoms. In addition, we have described the roles of mammalian sirtuins-with particular emphasis on their associations to aging, metabolism, and age related diseases with recent references. Current findings provide an understanding about mammalian sirtuins and their target diseases, small molecules discovery or drug discovery targeting sirtuin to tackle the serious diseases of aging.

Tuberculosis (TB) is an infectious disease caused by the pathogen Mycobacterium tuberculosis (M. tuberculosis), killing about two million people worldwide each year. An increase in the prevalence of drug-resistant strains of M. tuberculosis in the past decades has renewed focus on the development of new drugs that can treat both drug-sensitive and resistant TB infections. M. tuberculosis evades the host immune system and drug regimes by entering dormant phase within macrophage. As a consequence, there is a pressing need for new vaccines and antimicrobials to treat persistent infections. As clinically used antibiotics target very few essential functions of mycobacterium, it is rational that identification of new targets that are essential for bacterial growth and survival can serve as starting point for designing of novel drugs to cure both drug-sensitive and resistant TB infections. With the development of molecular biology and structural biology and the availability of the genome sequence of M. tuberculosis, some success has been achieved in the identification of new targets in M. tuberculosis and their relevant inhibitors. This review summarizes about ninety important targets that participate in a range of diverse physiological processes in M. tuberculosis and seven new drugs currently in clinical phase 2 or 3 trials. In addition, promising inhibitors with novel mechanisms of action and clinical vaccine candidates are highlighted.

The hypoxic microenvironment is a clinicopathological characteristic of many diseases, such as rheumatoid arthritis (RA). As a transcription factor activating the gene expression involved in processes such as cell metabolism and angiogenesis, hypoxia-inducible factor (HIF) has a central function in adaption to altered oxygen tension and even contributes to the progression of related diseases. In RA, HIF induces angiogenesis, cell migration, and cartilage destruction, inhibits the apoptosis of synovial cells and inflammatory cells and initiates glycolysis for energy supply by upregulating specific protein levels. HIF expression in RA can be regulated in both oxygen-dependent and independent fashions, leading to the aggravation of this disease. Therefore, HIF is one of the vital RA mediators. Based on the application of HIFtargeted drug research and development in tumors, HIF is a potential therapeutic target for treating RA.

Psoriasis is a multifactorial autoimmune skin disorder based on irregularities of the T- cell function. The abnormal keratinocyte hyper proliferation in psoriasis arises due to the activation of T-cells which produces rich amount of arachidonic acid leads to generation of various proinflammatory mediators like PGs, LTs, cytokines and adhesion molecules via MAPK/AP-1, EARK1/2 and protein kinase – C (PKCs) activation pathways. Incorporation of naturally occuring bioactives like, omega (ω) - 3 fatty acids (i.e., EPA and DHA) in a dose dependent manner results in inhibition of various pro-inflammatory mediators and metabolization of EPA and DHA leads to dampening of inflammation and higher resolution of the skin abnromalities. These all due to the promotion of the synthesis of ω-3 PUFA-derived lipid mediators viz namely resolvins and protectins. These have been widely used alone or in combination with other drugs in the treatment of psoriasis. Despite of their meritorious visages, the use of these bioactives is associated with several hiccups like higher unstability and vulnerable to degradation due to lipid peroxidation, poor and incosistent bioavilability by oral and topical administration. The potential use of nanomedicines in the delivery of such bioactives has gained wider attention owing to their promising bioavailability enhancement characteristics, improved stability and better efficacy. The present review gives an extensive account on ω-3 fatty acids (EPA and DHA) starting from seedling to apex, including biosynthesis, metabolites, and its mechanism of action in psoriasis. Moreover, barriers in the effective delivery of ω-3 fatty acids and how nanomedicines can be fit in the scope of its therapeutic delivery in psoriasis have also been addressed. Despite numerous advantages, application of EPA-DHA as ω-3 fatty acids therapeutics in the management of psoriasis are still at an initial stage. Nanomedicines approach to achieve high bioavailable delivery with safety and stability of ω-3 fatty acids showing the promising area for the future in psoriasis management.