A-kinase anchoring proteins as potential drug targets

A-kinase anchoring proteins (AKAPs) crucially contribute to the spatial and temporal control of cellular signalling. They directly interact with a variety of protein binding partners and cellular constituents, thereby directing pools of signalling components to defined locales. In particular, AKAPs mediate compartmentalization of cAMP signalling. Alterations in AKAP expression and their interactions are associated with or cause diseases including chronic heart failure, various cancers and disorders of the immune system such as HIV. A number of cellular dysfunctions result from mutations of specific AKAPs. The link between malfunctions of single AKAP complexes and a disease makes AKAPs and their interactions interesting targets for the development of novel drugs. LINKED ARTICLES This article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-2.     

Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases

New therapies directed at ameliorating or altering autoimmune diseases represent an area of significant medical need. Included amongst autoimmune diseases are problems related to transplantation rejection, as well as a number of neurological diseases such as Multiple Sclerosis (MS). A new group of molecular targets that may lead to novel therapies are lysophospholipid (LP) receptors. A large range of biological activities has been attributed to the actions of these simple phospholipids that include well-studied members lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). Documented cellular effects of these lipid molecules encompass growth-factor-like influences on cells, including but not limited to survival, migration, adhesion differentiation, as well as pathophysiological actions associated with cancer. In turn, these cellular effects have roles in developing and adult organ systems such as the nervous system, cardiovascular system, reproductive system and, of relevance here, the immune system. The mechanisms for these actions can be attributed to a growing family of cognate, 7-transmembrane G protein-coupled receptors (GPCRs), with documented validation through studies utilizing pharmacology, molecular genetics and an enlarging repertoire of chemical tools having agonist or antagonist properties. The growing literature on immunological effects of LP receptors, particularly those mediating the effects of S1P, has suggested possible therapeutic roles for this class of receptors. In particular, entry into humans of a non-selective S1P receptor agonist, FTY720, for kidney transplantation and possibly other indications (e.g., Multiple Sclerosis), has raised prospects for efficacious treatment of human diseases based on LP receptor targets. Here we provide a brief introduction to receptor-mediated lysophospholipid signaling and discuss its basic and potential therapeutic roles in autoimmune-related diseases.     

Structural and functional studies on proteins as potential drug discovery targets

Structural biology teaches us about the fundamental nature of biological molecules. Drug design is the most immediate medical application of structural biology. Therefore our studies have been focused on structural and functional studies of human disease-related proteins and proteins essential for the growth and development of pathogenic organisms. The present paper describes 1) structural biological studies of human autocrine motility factor, 2) structural biological studies of human ribonuclease L, and 3) structural biological studies of Plasmodium falciparum S-adenosyl- L-homocysteine hydrolase.     

Protein tyrosine phosphatases: their role in insulin action and potential as drug targets

Protein tyrosine phosphatases (PTPases) are the enzymes responsible for the selective dephosphorylation of tyrosine residues. PTPases function to regulate a wide array of biological responses mediated by growth factors and other stimuli by balancing the cellular level of phosphotyrosine in concert with their counterparts, protein tyrosine kinases. The important roles which PTPases play in regulating intracellular signalling and, ultimately, biological function along with the recent availability of information regarding their structural features has highlighted them as potential targets for pharmacological modulation. This is demonstrated by the increased level of activity directed towards the identification of novel small-molecule PTPase inhibitors. The rationale and potential utility of this drug discovery approach is discussed here, with particular emphasis on its application for the treatment of insulin resistance and Type 2 diabetes.     

Aquaporins as potential drug targets

The aquaporins (AQP) are a family of integral membrane proteins that selectively transport water and, in some cases, small neutral solutes such as glycerol and urea. Thirteen mammalian AQP have been molecularly identified and localized to various epithelial, endothelial and other tissues. Phenotype studies of transgenic mouse models of AQP knockout, mutation, and in some cases humans with AQP mutations have demonstrated essential roles for AQP in mammalian physiology and pathophysiology, including urinary concentrating function, exocrine glandular fluid secretion, brain edema formation, regulation of intracranial and intraocular pressure, skin hydration, fat metabolism, tumor angiogenesis and cell migration. These studies suggest that AQP may be potential drug targets for not only new diuretic reagents for various forms of pathological water retention, but also targets for novel therapy of brain edema, inflammatory disease, glaucoma, obesity, and cancer. However, potent AQP modulators for in vivo application remain to be discovered.     

Complement and complement regulatory proteins as potential molecular targets for vascular diseases

By-products of complement activation and complement regulatory proteins are increasingly recognized to play an important pathogenic role in a variety of vascular diseases including atherosclerosis, ischemia and reperfusion injury, hyperacute graft rejection, vasculitis, and the vascular complications of human diabetes. "Self" damage by autologous complement is mediated by activation products of the complement cascades or by direct insertion of the membrane attack complex (MAC) into cell membranes. Specifically, insertion of MAC complexes into endothelial cells results in the release of an array of growth factors and cytokines that induces proliferation, inflammation and thrombosis in the vascular wall. This paper reviews complement and complement regulatory proteins with specific focus on the vasculature and vascular diseases; it highlights complement and its regulators as potential targets for the rational design of mechanism-specific drugs for the treatment of some of the most prevalent human diseases.     

Diacylglycerol kinases as emerging potential drug targets for a variety of diseases

Diacylglycerol (DAG) kinase (DGK) modulates the balance between the two signaling lipids, DAG and phosphatidic acid (PA), by phosphorylating (consuming) DAG to yield PA. Ten mammalian DGK isozymes have been identified to date. In addition to two or three cysteine-rich C1 domains (protein kinase C-like zinc finger structures) commonly conserved in all DGKs, these isoforms possess a variety of regulatory domains of known and/or predicted functions, such as a pair of EF-hand motifs, a pleckstrin homology domain, a sterile alpha motif domain, a MARCKS (myristoylated alanine-rich C kinase substrate) phosphorylation site domain and ankyrin repeats. Recent studies have revealed that DGK isozymes play pivotal roles in a wide variety of mammalian signal transduction pathways conducting growth factor/cytokine-dependent cell proliferation and motility, seizure activity, immune responses, cardiovascular responses and insulin receptor-mediated glucose metabolism. It is suggested that several DGK isozymes can serve as potential drug targets for cancer, epilepsy, autoimmunity, cardiac hypertrophy, hypertension and type II diabetes. Unfortunately, there are no DGK isozyme-specific inhibitors/activators at present. Development of these compounds is eagerly awaited for the development of novel drugs targeting DGKs.     

Annexins as potential targets in ocular diseases

Annexins (AnxAs) are Ca²⁺/phospholipid-binding proteins extensively studied and generally involved in several diseases. Although evidence exists regarding the distribuition of AnxAs in the visual system, their exact roles and the exact cell types of the eye where these proteins are expressed are not well-understood. AnxAs have pro-resolving roles in infectious, autoimmune, degenerative, fibrotic and angiogenic conditions, making them an important target in ocular tissue homeostasis. This review summarizes the current knowledge on the distribution and function of AnxA1–8 isoforms under normal and pathological conditions in the visual system, as well as perspectives for ophthalmologic treatments, including the potential use of the AnxA1 recombinant and/or its mimetic peptide Ac_2–26.     

Bcl-2-related proteins as drug targets

The Bcl-2 family of proteins provide the most unambiguous link between mitochondrial functions and apoptosis, as their only (or principal) functions appear to be as regulators of this cell death pathway. Rational drug design to manipulate the functions of these proteins has been hampered by the lack of a clear understanding of a biochemical or molecular function, with disruption of intra-family protein-protein interactions as the only known, but daunting, objective. There has been substantial progress in this task using molecular modeling and drug leads. The prospects are also good for development of chemical tools for functional analysis of the Bcl-2 proteins.     

Mitochondrial dynamics proteins as emerging drug targets

The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant mitochondrial fusion or fission that is often a consequence of deregulated mitochondrial dynamics proteins; however, pharmacological targeting of these proteins has been lacking and is challenged by complex molecular mechanisms. Recent studies have advanced our understanding in this area and have enabled rational drug design and chemical screening strategies. We provide an updated overview of the regulatory mechanisms of fusion and fission proteins, their structure–function relationships, and the discovery of pharmacological modulators demonstrating their therapeutic potential. These advances provide exciting opportunities for the development of prototype therapeutics for various diseases.     

Purinergic and pyrimidinergic receptors as potential drug targets

In the last decade, the field of purinergic pharmacology has continued to grow as the complexity of the receptor families and the various enzymes involved in purine metabolism have been defined in molecular terms. A major theme that has emerged from these studies is the functional complexity of the interactions between P1 and P2 receptors, based upon the dynamic interrelationship between ATP and adenosine as extracellular signaling molecules. It is now clear that ATP and its degradation products (particularly ADP and adenosine) form a complex cascade for the regulation of cell-to-cell communication that can function to attenuate the consequences of tissue trauma (e.g. ischemia) that involve alterations in cellular energy charge and depletion of ATP stores. In addition to the P2 receptor family, alterations in cellular ATP stores can also affect the function of other receptors, e.g. K(ATP) channels, and mitochondrial function. The discovery of pyrimidine-preferring (UTP/UDP) P2Y receptors has also raised the possibility that the corresponding nucleoside, uracil, may function as a signaling molecule.     

Hepatitis C virus proteins as targets for drug development: the role of bioinformatics and modelling

Hepatitis C virus (HCV), a member of the Flaviviridae family, has been recognised to be responsible for both parenterally transmitted and sporadic non-A and non-B hepatitis affecting 1-3% of the world population. HCV is a positive stranded RNA virus encoding a single polyprotein which contains at least ten unique structural and non-structural proteins. Amongst these the structural protein E2 has been of special interest for vaccine development and the serine protease NS3, which is responsible for cleavage of the polyprotein, for the development of small molecule inhibitors. We will focus on the contribution of computational techniques and the use of structural information for the design and discovery of novel therapeutic agents for these targets. Both drug discovery and vaccine design efforts will be discussed taking into account also the problem of emerging resistance.     

Endothelial progenitor cells as potential drug targets

Endothelial progenitor cells (EPC) are bone marrow derived cells with the potential to differentiate into mature functional endothelial cells. First clinical trials have been performed investigating the effects of EPC transplantation into cardiac ischemic areas after myocardial infarction, in patients with peripheral atherovascular disease or on endothelialisation of artificial heart valves. Next to EPC transplantation, the pharmacological mobilisation and functional modification of EPC may also play a major role in future therapies. Studies have raised the concern that patients with coronary heart disease or severe heart failure may suffer from decreased amounts and impaired function of peripheral circulating EPC. Drug induced mobilization of EPC and normalization of EPC function may therefore improve prognosis of certain cardiovascular diseases. The underlying molecular events of a disturbed mobilisation, differentiation, homing and/or function of EPC are not well understood. In the present review we will highlight the current knowledge of the role of EPC dysfunction in various cardiovascular diseases and focus on potential causally related molecular mechanisms, which might be novel drug targets.