Screening the receptorome yields validated molecular targets for drug discovery

With the recently completed sequencing and annotation of the human genome, it has become clear that a significant portion of the genome encodes signal-transducing molecules including receptors, protein kinases, ion channels, transporters and coupling proteins. This review focuses on membrane-localized receptors, which represent the largest single group of signal-transducing molecules. Indeed, one can estimate that nearly 10% of the human genome encodes membrane-localized receptors (e.g. G-protein coupled receptors, ligand-gated ion channels and transporters). We have defined that portion of the human genome that encodes 'receptors' the receptorome. In this article, we will demonstrate how the massively parallel screening of the receptorome provides a facile and under-utilized screening platform for drug discovery. Using case studies, we will show how receptorome-based screening elucidates the mechanisms responsible for serious side-effects of both approved and investigational medications. Additionally, we will provide evidence that receptorome-based screening provides insights into novel therapeutic indications of approved medications and serves to validate targets for therapeutic drug discovery.     

Screening the receptorome: an efficient approach for drug discovery and target validation

The receptorome, comprising at least 5% of the human genome, encodes receptors that mediate the physiological, pathological and therapeutic responses to a vast number of exogenous and endogenous ligands. Not surprisingly, the majority of approved medications target members of the receptorome. Several in silico and physical screening approaches have been devised to mine the receptorome efficiently for the discovery and validation of molecular targets for therapeutic drug discovery. Receptorome screening has also been used to discover, and thereby avoid, the molecular targets responsible for serious and unforeseen drug side effects.     

Molecular targets for axon regeneration: focus on the intrinsic pathways

Axonal damage and degeneration are prominent components of acute neurological disorders such as stroke, brain and spinal cord injuries, leading to the dysfunction of neuronal networks, which is largely responsible for the impaired neurological function. In the CNS, injured axons not only degenerate but are unable to regenerate and have a limited capacity to sprout and re-establish lost connections. Therefore, axonal damage often results in long term disability. Strategies aimed at fostering neurological recovery by promoting axonal sprouting and regeneration have largely targeted the glial inhibitory environment that develops following central nervous system injury. However, experimental evidence suggests that providing a favorable environment may not be the sole and sufficient means for functional regeneration, and that activating the limited intrinsic potential of neurons to sprout and regenerate may represent an alternative and complementary therapeutic approach. Experimental data that show how the modulation of the intrinsic potential of neurons can promote axonal sprouting and regeneration in the CNS are presented and discussed. These data may suggest future therapeutic opportunities to promote recovery in acute neurological disorders.     

Premature ejaculation: focus on therapeutic targets

Background: Premature ejaculation (PE) is poorly defined but the most common male sexual complaint. It can be treated with strategies including oral pharmacotherapy, topical anaesthetics, behavioural therapy and surgery. Although PE is treatable in most, but not all, patients by currently available modalities, long term success rates have been disappointing. An approved treatment so far does not exist. Objective: To review literature on the current and potential therapeutic targets for PE. Methods: Available English–language published literature is reviewed. Results/conclusions: There are many targets for future therapeutic approaches to PE that may address the shortcomings of existing therapy. Selecting the best targets depends heavily on their playing a prominent role in PE. Exploiting the full therapeutic potential of these targets will require additional basic and clinical research.     

Emerging targets for the pharmacological treatment of depression: focus on melatonergic system

Depression is a disabling condition which adversely affects a person's family, social and work life, and that is associated with a heavy burden to society. Although the available antidepressants have shown their effectiveness and have greatly improved the prognosis of the disorder, the current management of depression is far from being satisfactory. In the last years, besides the classical research involving serotonin, norepineprine and dopamine, non-monoaminergic mechanisms have been explored in the attempt to discover new antidepressants. One such innovative approach focused on melatonergic system, as melatonin is involved in synchronizing circadian rhythms, which are known to be altered in depression. This narrative review aims to provide a comprehensive overview of different aspects of the melatonergic system, including biochemical and anatomical characteristics, impact on the sleep/wake system, and implications for the treatment of depression. In particular, the observation that melatonin may promote sleep and synchronize the internal clock led to development of high-affinity agonists for melatonin receptors (MT). Agomelatine, a naphthalene bioisostere of melatonin, which combines a potent MT1 and MT2 agonism with 5-HT(2C) receptor antagonism, has been found to be effective in the treatment of depressive and anxiety symptoms associated with major depression, with rapid and beneficial effects on the regulation of sleep continuity and quality. If substantiated by further evidence, the observation that melatonergic system dysfunctions contribute to the development of depression, as well as that the antidepressant action of agomelatine is linked to its binding properties to MT1/MT2 receptors, might open new avenues for the discovery of antidepressive agents.     

Nitric oxide-derived oxidants with a focus on peroxynitrite: molecular targets, cellular responses and therapeutic implications

Nitric oxide participates in a wide array of physiological processes, ranging from neurotransmission to precursor of cytotoxic effector molecules of the immune system. Although nitric oxide is a mildly reactive intermediary, it can act as a precursor of strong oxidants under pathological conditions associated with oxidative stress including cardiovascular, inflammatory and neurodegenerative disorders. Peroxynitrite, the reaction product of nitric oxide with superoxide radicals, emerges as one of the principal players of nitric oxidederived toxicity due to its facile formation and ability to react with several critical cellular targets including, thiols, proteins, lipids and DNA. The extent of "nitroxidative stress" is determined by several factors, including the concentration and exposure time to this reactive species or its derived radicals and by the ability of the cell to face the oxidative challenge by means of its antioxidant defenses. The inflicted biomolecular damage can result on minimal and reversible changes to cell and tissue physiology, to alteration in bioenergetics, disruption of DNA integrity, mitochondrial dysfunction and even cell death. Although dissecting the free radical chemistry pathways responsible of cell/tissue disturbance of oxidative signaling and promotion of oxidative damage arising from nitric oxide-derived oxidants in a biological context is a vast endeavor, is an ineludible task in order to generate a rational therapeutic approach to modulate nitroxidative stress. Several redox-based pharmacological strategies with a collection of compounds with varying mechanisms of action have been tested at the cellular, preclinical and even clinical levels, and some novel and promising developments are underway. This review deals with key kinetic and biochemical aspects of nitric oxide-derived oxidant formation and reactions in biological systems, emphasizing the current evidence at the biochemical, cell/tissue and animal/human levels that support a pathophysiological role for peroxynitrite and related species in human pathology. In addition, a selection of available pharmacological tools will be discussed as an effort to rationalize antioxidant and/or redox-based therapeutic interventions in disease models.     

Neuroimmune interactions and pain: focus on glial-modulating targets

Chronic pain is the most difficult type of pain to treat. Previously, the development of analgesics has focused on neuronal targets; however, current analgesics are only modestly effective, have significant side effects and do not provide universal efficacy. New strategies are needed for the development of more effective analgesics. Glial cells have integral roles in CNS homeostasis, and chronic pain etiology and progression. In this review, the role of glia in neuropathic pain and opioid administration is described, as well as the potential superior efficacy and wider therapeutic indices provided by drugs that modulate specific glial function via novel targets.     

Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect

The histone deacetylase inhibitors (HDACi) have demonstrated anticancer efficacy across a range of malignancies, most impressively in the hematological cancers. It is uncertain whether this clinical efficacy is attributable predominantly to their ability to induce apoptosis and differentiation in the cancer cell, or to their ability to prime the cell to other pro-death stimuli such as those from the immune system. HDACi-induced apoptosis occurs through altered expression of genes encoding proteins in both intrinsic and extrinsic apoptotic pathways; through effects on the proteasome/aggresome systems; through the production of reactive oxygen species, possibly by directly inducing DNA damage; and through alterations in the tumor microenvironment. In addition HDACi increase the immunogenicity of tumor cells and modulate cytokine signaling and potentially T-cell polarization in ways that may contribute the anti-cancer effect in vivo. Here, we provide an overview of current thinking on the mechanisms of HDACi activity, with attention given to the hematological malignancies as well as scientific observations arising from the clinical trials. We also focus on the immune effects of these agents.     

Molecular targets in immune-mediated diseases: focus on rheumatoid arthritis

There are a large number of diseases involving inappropriate activation of the immune system. This review focuses on one such disease, rheumatoid arthritis (RA). Over recent years there has been a dramatic shift in the treatment of RA, in which biological agents, such as monoclonal antibodies and immuno-fusion proteins, have offered the potential to enhance or replace conventional immunosuppressive therapies. This review covers some of the novel biological molecules currently under investigation as potential therapeutic targets in RA. In addition, it covers the genomic and proteomic strategies being used to identify potential new molecular targets for future therapies. Selectively blocking the immune response, in a combination approach blocking not only inflammation but also the adaptive memory response and tissue destruction, holds great promise for the treatment of RA and many other immune-mediated diseases.     

Molecular targets in immune-mediated diseases: focus on rheumatoid arthritis

There are a large number of diseases involving inappropriate activation of the immune system. This review focuses on one such disease, rheumatoid arthritis (RA). Over recent years there has been a dramatic shift in the treatment of RA, in which biological agents, such as monoclonal antibodies and immuno-fusion proteins, have offered the potential to enhance or replace conventional immunosuppressive therapies. This review covers some of the novel biological molecules currently under investigation as potential therapeutic targets in RA. In addition, it covers the genomic and proteomic strategies being used to identify potential new molecular targets for future therapies. Selectively blocking the immune response, in a combination approach blocking not only inflammation but also the adaptive memory response and tissue destruction, holds great promise for the treatment of RA and many other immune-mediated diseases.     

Genetic targets for the treatment of pituitary adenomas: focus on the pituitary tumor transforming gene

The pituitary tumor transforming gene (PTTG) has been identified as a key protein in mitotic regulation. The hypothesis that PTTG overexpression results in genetic instability has been strengthened by the recent observation of inappropriate and aneuploid cell division in cell lines expressing high levels of PTTG. PTTG transactivates the oncogene c-myc, which in turn may influence cell growth. A direct link between PTTG, basic fibroblast growth factor and angiogenesis has been demonstrated.     

The medical uses and side effects of etanercept with a focus on cutaneous disease

Etanercept is a dimeric fusion protein that has been approved for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, active ankylosing spondylitis and moderate to severe plaque psoriasis. It has been reported to be useful in other variants of psoriasis, Still's disease, recurrent aphthous ulcers, and a variety of rare cutaneous conditions. Its cutaneous side effects are rare and include injection site reactions, cutaneous lupus, and cutaneous vasculitis. Its systemic side effects are also rare and include induction or worsening of infections, lupus, multiple sclerosis, and congestive heart failure. Linkage to an increased risk of lymphoma is unclear. In short, etanercept is a promising medication with substantial benefits and use will probably increase in the future. This review surveys off-label uses and side effects of etanercept.