PPAR delta as a therapeutic target in metabolic disease

PPAR delta is the only member in the PPAR subfamily of nuclear receptors that is not a target of current drugs. Animal studies demonstrate PPAR delta activation exerts many favorable effects, including reducing weight gain, increasing skeletal muscle metabolic rate and endurance, improving insulin sensitivity and cardiovascular function and suppressing atherogenic inflammation. These activities stem largely from the ability of PPAR delta to control energy balance, reduce fat burden and protect against lipotoxicity caused by ectopic lipid deposition. Therefore, PPAR delta represents a novel therapeutic target and the development of PPAR delta gonists/modulators may be useful for treating the whole spectrum of metabolic syndrome.     

Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer

AMP-activated protein kinase (AMPK) is a cellular energy sensor activated by metabolic stresses that either inhibit ATP synthesis or accelerate ATP consumption. Activation of AMPK in response to an increase in the cellular AMP:ATP ratio results in inhibition of ATP-consuming processes such as gluconeogenesis and fatty acid synthesis, while stimulating ATP-generating processes, including fatty acid oxidation. These alterations in lipid and glucose metabolism would be expected to ameliorate the pathogenesis of obesity, type 2 diabetes and other metabolic disorders. Recently, AMPK has also been identified as a potential target for cancer prevention and/or treatment. Cell growth and proliferation are energetically demanding, and AMPK may act as an “energy checkpoint” that permits growth and proliferation only when energy reserves are sufficient. Thus, activators of AMPK could have potential as novel therapeutics both for metabolic disorders and for cancer, which together constitute two of the most prevalent groups of diseases worldwide.     

The ribosome as a drug target

The elucidation of the crystal structure of the ribosome and its subunits has dramatically increased our understanding of this organelle and the molecular interactions that determine its functional capabilities. Two recent publications, one on the structure of the bacterial ribosome at 3.5A resolution and one on the identification of functionally relevant sites within the small subunit rRNA, illustrate the importance of interdisciplinary approaches in exploiting the ribosome as a drug target.     

PPAR: a therapeutic target in Parkinson's disease

Parkinson's disease (PD) is a progressive and chronic neurodegenerative disorder, characterized by progressive loss of dopaminergic neurons in substantia nigra. The etiology and pathogenesis of PD is still elusive, however, a large body of evidence suggests a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction in the pathogenesis of PD. Due to multifactorial nature of the disease, currently available drug therapy cannot halt / slow down the disease progression, and only provides symptomatic relief. Peroxisome proliferator-activated receptor (PPAR), a member of nuclear receptor superfamily, regulates development, tissue differentiation, inflammation, mitochondrial function, wound healing, lipid metabolism and glucose metabolism. Recently, several PPAR agonists were shown to exert neuroprotective activity against oxidative damage, inflammation and apoptosis in several neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis and multiple sclerosis. Similarly, regular intake of PPAR activating non-steroidal anti-inflammatory drugs such as indomethacin and ibuprofen was associated with reduced incidence and progression of neurodegenerative disorders in several epidemiological studies. In this article, we review studies relating to the neuroprotective effect of PPAR agonists in in vitro and in vivo models of PD. Similarly, the pharmacological mechanism in neuroprotective actions of PPAR agonists is also reviewed. In conclusion, PPAR agonists exert neuroprotective actions by regulating the expression of a set of genes involved in cell survival processes, and could be a therapeutic target in debilitating neurodegenerative illnesses such as PD.     

Dopamine and dopamine receptors as target sites for cardiovascular drug action

It is controversial whether dopamine (DA) is a peripheral neurotransmitter in the cardiovascular/renal system. The endogenous concentration of DA in the heart and blood vessels is generally only a fraction (5%) of that of norepinephrine (NE). With perhaps the exception of the kidney, the majority of the evidence suggests a precursor role for this amine rather than that of a neurotransmitter. The main weakness of arguments favoring DA as a vascular neurotransmitter is relative lack of data showing selective DA release and lack of effects of selective DA antagonists on neural stimulation. However, DA receptors have been characterized in cardiovascular tissues and are of two types: DA1 receptors located on vascular smooth muscle (postjunctional), which appear to mediate relaxation of the muscle, and DA2 receptors located on sympathetic nerves (pejunctional), which inhibit NE release. These receptors are interesting and potential target sites for novel cardiovascular drug action for the treatment of hypertension and renal ischemia. Moreover, selective DA receptor agonists will be important tools in understanding the role of DA receptors in normal and disease states.     

PPAR gamma as a metabolic regulator: insights from genomics and pharmacology

Since its identification in the early 1990 s, peroxisome-proliferator-activated receptor gamma (PPAR gamma), a nuclear hormone receptor, has attracted tremendous scientific and clinical interest. The role of PPAR gamma in macronutrient metabolism has received particular attention, for three main reasons: first, it is the target of the thiazolidinediones (TZDs), a novel class of insulin sensitisers widely used to treat type 2 diabetes; second, it plays a central role in adipogenesis; and third, it appears to be primarily involved in regulating lipid metabolism with predominantly secondary effects on carbohydrate metabolism, a notion in keeping with the currently in vogue 'lipocentric' view of diabetes. This review summarises in vitro studies suggesting that PPAR gamma is a master regulator of adipogenesis, and then considers in vivo findings from use of PPAR gamma agonists, knockout studies in mice and analysis of human PPAR gamma mutations/polymorphisms.     

Ghrelin as a target for gastrointestinal motility disorders

The therapeutic potential of ghrelin and synthetic ghrelin receptor (GRLN-R) agonists for the treatment of gastrointestinal (GI) motility disorders is based on their ability to stimulate coordinated patterns of propulsive GI motility. This review focuses on the latest findings that support the therapeutic potential of GRLN-R agonists for the treatment of GI motility disorders. The review highlights the preclinical and clinical prokinetic effects of ghrelin and a series of novel ghrelin mimetics to exert prokinetic effects on the GI tract. We build upon a series of excellent reviews to critically discuss the evidence that supports the potential of GRLN-R agonists to normalize GI motility in patients with GI hypomotility disorders such as gastroparesis, post-operative ileus (POI), idiopathic chronic constipation and functional bowel disorders.     

Banking on ATM as a new target in metabolic syndrome

In this issue of Cell Metabolism, Semenkovich and his colleagues show that ATM, a protein well known for its roles in the cellular response to DNA breaks, may also be linked to metabolic and cardiovascular diseases (Schneider et al., 2006). ATM seemingly does this by inhibiting JNK, a stress kinase involved in inflammation with related effects in insulin resistance and atherosclerosis. In an interesting twist, the authors show that chloroquine, an antimalarial drug, also activates ATM, which inhibits JNK, and improves insulin sensitivity and cardiovascular effects. These findings provide potential new insights into the pathogenesis and treatment of metabolic syndrome.     

Neural melanocortin receptors in obesity and related metabolic disorders

Obesity is a global health issue, as it is associated with increased risk of developing chronic conditions associated with disorders of metabolism such as type 2 diabetes and cardiovascular disease. A better understanding of how excessive fat accumulation develops and causes diseases of the metabolic syndrome is urgently needed. The hypothalamic melanocortin system is an important point of convergence connecting signals of metabolic status with the neural circuitry that governs appetite and the autonomic and neuroendocrine system controling metabolism. This system has a critical role in the defense of body weight and maintenance of homeostasis. Two neural melanocortin receptors, melanocortin 3 and 4 receptors (MC3R and MC4R), play crucial roles in the regulation of energy balance. Mutations in the MC4R gene are the most common cause of monogenic obesity in humans, and a large literature indicates a role in regulating both energy intake through the control of satiety and energy expenditure. In contrast, MC3Rs have a more subtle role in energy homeostasis. Results from our lab indicate an important role for MC3Rs in synchronizing rhythms in foraging behavior with caloric cues and maintaining metabolic homeostasis during periods of nutrient scarcity. However, while deletion of the Mc3r gene in mice alters nutrient partitioning to favor accumulation of fat mass no obvious role for MC3R haploinsufficiency in human obesity has been reported. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.     

Glutamate racemase as a target for drug discovery

The bacterial cell wall is a highly cross‐linked polymeric structure consisting of repeating peptidoglycan units, each of which contains a novel pentapeptide substitution which is cross‐linked through transpeptidation. The incorporation of d ‐glutamate as the second residue is strictly conserved across the bacterial kingdom. Glutamate racemase, a member of the cofactor‐independent, two‐thiol‐based family of amino acid racemases, has been implicated in the production and maintenance of sufficient d ‐glutamate pool levels required for growth. The subject of over four decades of research, it is now evident that the enzyme is conserved and essential for growth across the bacterial kingdom and has a conserved overall topology and active site architecture; however, several different mechanisms of regulation have been observed. These traits have recently been targeted in the discovery of both narrow and broad spectrum inhibitors. This review outlines the biological history of this enzyme, the recent biochemical and structural characterization of isozymes from a wide range of species and developments in the identification of inhibitors that target the enzyme as possible therapeutic agents.     

Adenosine receptors as a new target for resveratrol-mediated glioprotection

Resveratrol, a natural polyphenolic compound, has been studied as a neuroprotective molecule. Our group has demonstrated that such effect is closely associated with modulation of glial functionality, but the underlying mechanisms are not fully understood. Because astrocytes actively participate in the brain inflammatory response, and activation of adenosine receptors can attenuate inflammatory processes, the aim of this study was to investigate the role of adenosine receptors as a mechanism for resveratrol glioprotection, particularly regarding to neuroinflammation. Therefore, primary astrocyte cultures were co-incubated with resveratrol and selective antagonists of A₁, A_2A, and A₃ adenosine receptors, as well as with caffeine (a non-selective adenosine receptor antagonist), and then challenged with bacterial inflammogen lipopolysaccharide (LPS). Caffeine and selective adenosine receptor antagonists abolished the anti-inflammatory effect of resveratrol. In accordance with these effects, resveratrol prevented LPS-induced decrease in mRNA levels of adenosine receptors. Resveratrol could also prevent the activation of pro-inflammatory signaling pathways, such as nuclear factor κB (NFκB) and p38 mitogen-activated protein kinase (p38 MAPK) in a mechanism dependent on adenosine receptors. Conversely, trophic factors and protective signaling pathways, including sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and phosphoinositide 3-kinase (PI3K)/Akt were positively modulated by resveratrol in both LPS-stimulated and unstimulated astrocytes, but adenosine receptor antagonism did not abrogate all effects of resveratrol. To our knowledge, our data provide the first evidence that adenosine receptors are involved in the anti-inflammatory activity of resveratrol in astrocytes, thus exerting an important role for resveratrol-mediated glioprotection.     

Viral protein cleavages as a drug design target.

Many animal and plant viruses encode proteolytic enzymes which are involved in regulation of viral replication and assembly. The proteases are becoming well-characterized, and offer attractive features for the design of selective antiviral agents. Approaches to the assay of viral protease inhibitors and the various classes identified are described.     

Mitosis as an anti-cancer drug target

Suppression of cell proliferation by targeting mitosis is one potential cancer intervention. A number of existing chemotherapy drugs disrupt mitosis by targeting microtubule dynamics. While efficacious, these drugs have limitations, i.e. neuropathy, unpredictability and development of resistance. In order to overcome these issues, a great deal of effort has been spent exploring novel mitotic targets including Polo-like kinase 1, Aurora kinases, Mps1, Cenp-E and KSP/Eg5. Here we summarize the latest developments in the discovery and clinical evaluation of new mitotic drug targets.     

Adenosine receptors as drug targets

There are four adenosine receptors, A₁, A_2A, A_2B and A₃, together forming a defined subgroup of G protein coupled receptors. They are well conserved and widely expressed. The endogenous agonist, adenosine, has a minimal concentration in body fluids (20-200 nM) that is sufficient to slightly activate the receptors where they are very highly expressed—as in the basal ganglia, on fat cells and in the kidney. Here adenosine can play a physiological role and here antagonists such as caffeine can have effects in healthy individuals. Adenosine levels rise in stress and distress (up to 30 μM in ischemia) and tend to minimize the risk for adverse outcomes by increasing energy supply and decreasing cellular work, by stimulating angiogenesis, mediating preconditioning and having multiple effects on immune competent cells. These pathophysiological roles of adenosine also offer some potential drug targets, but the fact that adenosine receptors are involved in so many processes does not simplify drug development.