Current Medicinal Chemistry - Volume 14, Issue 22, 2007

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) belong to the protein family of neurotrophins. They both display profound neuromodulatory functions and are essentially involved in the survival and homeostatic maintenance of central and peripheral neurons during development and adulthood. Moreover, NGF and BDNF are known to modulate immune cell function and thus serve as mediators in the reciprocal cross talk between neurons and immune cells. Neurotrophic factors have been implicated in pathophysiological mechanisms of many diseases of the nervous and the immune system, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), neuropathy, pain, allergic bronchial asthma (BA) and neurotrophic keratitis. For all these diseases research has reached the point of creating strategies for therapeutic intervention with neurotrophins. In this review, we present an overview of the pathophysiology, therapeutic interventions and strategies concerning NGF and BDNF in the mentioned diseases.

The loss of the neurotransmitter noradrenaline occurs constantly in Parkinson's disease. This is supposed to worsen disease progression, either by increasing the vulnerability of dopamine-containing neurons or by reducing the recovery once they are damaged. Novel data also show that the loss of noradrenergic innervation facilitates the onset of dyskinesia occurring in Parkinsonian patients during dopamine replacement therapy. In the first part of the manuscript we review the evidence showing the loss of the noradrenergic system as an early event in the natural history of Parkinsonism. This evidence is discussed in light of novel reports showing the deleterious effects produced by the noradrenergic deficit on the survival of nigral dopamine neurons. In particular, we analyze the biochemical and morphological changes produced in the nigrostriatal system by the loss of endogenous noradrenaline. In a dedicated paragraph we specifically evaluate the cross affinity between dopamine and noradrenaline systems. In fact, this is critical during dopamine/noradrenaline replacement therapy in Parkinson's disease. In the last part, we overview novel therapeutic approaches aimed at restoring the activation of noradrenaline receptors to reduce the dyskinesia occurring in the treatment of Parkinson's disease.

Improvements in our understanding of the functions of peroxisome proliferator-activated receptor (PPAR) subtypes as master regulators of many biological functions have made it possible to develop novel PPAR ligands with characteristic subtype selectivity as biochemical tools and/or candidatedrugs for the treatment of PPAR-dependent diseases such as metabolic syndrome, which includes type II diabetes, dyslipidemia, obesity, hypertension, and inflammation. Based on the findings that the glitazone-class antidiabetic agents, and fibrate-class antidyslipidemic agents are ligands of PPARγ and PPARα respectively, much research interest has been focused on these two subtypes as therapeutic targets for the treatment of type II diabetes and dyslipidemia. In contrast, research interest in PPARδ has been limited. However, since 2001, the availability of PPARδ knockout animals and selective ligands has led to the uncovering of possible roles of PPARδ in fatty acid metabolism, insulin resistance, reverse cholesterol transport, inflammation, and so on. It has become clear that ligands able to modulate PPARδ-mediated pathways are candidates for the treatment of altered metabolic function. This review focuses on recent medicinal chemical studies to identify PPARδ-selective agonists.

Knowledge of the structure and dynamics of proteins and protein assemblies is critical both for understanding the molecular basis of physiological and patho-physiological processes and for guiding drug design. While X-ray crystallography and nuclear magnetic resonance spectroscopy are both excellent techniques for this purpose, both suffer from limitations, including the requirement for high quality crystals and large amounts of material. Recently, hydrogen/deuterium exchange measured using mass spectrometry (HXMS) has emerged as a powerful new tool for the study of protein structure, dynamics and interactions in solution. HXMS exploits the fact that backbone amide hydrogens can exchange with deuterium when a protein is incubated in D2O, and that the rate of the exchange process is highly dependent on the local structural environment. Several features of HXMS make it an especially attractive approach, including small sample requirements and the ability to study extremely large protein assemblies that are not amenable to other techniques. Here, we provide an overview of HXMS and describe several recent applications to problems of medical interest. After reviewing the molecular basis of the H/D exchange process, the different steps of the HXMS experiment - labeling, rapid proteolysis, fragment separation and mass measurement - are described, followed by a discussion of data analysis methods. Finally, we describe recent results on the application of HXMS to 1) mapping drug/inhibitor binding sites and detecting drug induced conformational changes, 2) studying viral capsid structure and assembly, and 3) characterizing the structure of pathological protein conformations, specifically amyloid fibrils.

De novo lymphangiogenesis influences different pathological courses via modulating tissue fluid homeostasis, macromolecule absorption, and leukocyte transmigration. During the past decade, improved understanding of lymphatic biology, especially VEGF-C/- D/VEGFR-3-mediating lymphangiogenesis has substantially promoted clinical research in lymphatic insufficiency. The role of lymphangiogenesis in the setting of the inflammatory processes observed in transplants, inflamed cornea, wound healing, acquired lymphedema and tumor invasion, however, remains to be elucidated. The chemokine family of peptide chemoattractants and other mediators, e.g., CCL21-CCR7, D6, NF-κB and TNF-α may be important contributors to pathophysiological changes of lymphatic endothelial cells (LECs) and inflammatory lymphangiogenesis. Dendritic cells and macrophages may also involve in LEC proliferation and differentiation. Increased knowledge of LEC-specific modulators in inflammatory microenvironment is vital for prevention and treatment of lymphatic- associated diseases.

Apoptosis is involved in a wide range of pathologic conditions, including neurodegenerative, autoimmune diseases, cardiovascular diseases and cancer. Therefore, the ability to understand and manipulate the cell death machinery is an obvious goal of medical research. Novel therapeutic approaches to modulate disease by regulating apoptosis are being tested in preclinical and clinical settings. Approaches include the traditional use of small molecules to target specific players in the apoptosis cascade. As our understanding of apoptosis increases, further opportunities will arise for tailor-made therapies that will result in improved clinic. From variety of compounds are discovered in this field and only few are found in the preclinical and clinical trials. The lack of specific potent nonpeptide apoptosis inducers and/or inhibitors has limited for a long time the clinical investigation of this target. But in the last few years the renewed interest of pharmaceutical companies has been giving a strong impulse to the research in this area. This review considers the molecular mechanisms of apoptosis and their interaction in regulation of apoptosis. We also focus on recent developments of nonpeptide apoptosis modulators and their progress in drug lead discovery.

The process of developing drugs dates to antiquity. The herbal formulations during the old days were more traditional than with any scientific rationale. As different branches of physics, chemistry and biology started revealing the physiological processes in molecular details and as the sophisticated methods for probing into these phenomena were innovated, the processes of drug development changed significantly. However, the very first step in the process which is defining a drug target remains a major hurdle. The classical methods that predate the functional genomics and proteomics involve a cumbersome, painstaking detailing of a given enzyme or a receptor, followed by its validation as a target. The sophisticated methods in the post-genomic and proteomic era reduced the time taken to define targets, but the speed of drug discovery is not necessarily as quick as it promised. This is primarily due to prolific predictions pressing validation too hard, although both non-robotic and robotic high throughput screenings match with the requirement. Since these drugs target pathogens, a serious disadvantage with these methodologies is the emergence of drug resistance. Therefore, we propose a functional approach whereby the host-pathogen interaction is studied to find out the alterations in immune responses, the profile of host gene expression and activation of cell signaling molecules, the kinases in particular. Such interactions often induce the expression of those genes and activation of those proteins which are required for their survival. We demonstrate that reversal of such profiles of gene expression and protein activation ameliorates the infection. Therefore, those gene products and the kinases with pro-parasitic functions can serve as targets.

Two-thirds of stroke deaths worldwide occur in developing countries. The higher prevalence of undernutritional states and parasitic infestations in many of these countries could lead to vitamin B12 and folate deficiencies. Hyperhomocysteinemia, a proxy measure for the nutritional status of B vitamins, has been reported in many developing countries and is found to be associated with nutritionrelated low plasma folate and vitamin B12. Several epidemiological observations have linked hyperhomocysteinemia to increased risk for stroke. The exact molecular mechanism by which homocysteine promotes atherothrombosis is not clear, although several possible roles have been suggested. Homocysteine is believed to cause atherogenesis and thrombogenesis via endothelial damage, focal vascular smooth muscle proliferation probably causing irregular vascular contraction, and coagulation abnormalities. Supplementation with the nutrient cofactors required for optimal functioning of the homocysteine metabolic pathways significantly impacts plasma homocysteine levels, and offers a new integrated possibility for prevention of stroke in the underdeveloped and rapidly developing countries.

Periodontitis is bacterial infection of tooth-supporting tissues leading to inflammation and, subsequently, to loss of teeth. It is one of the most common infections worldwide. Recent studies have shown that periodontal infection may pose a threat to general health by increasing the risk of cardiovascular and lung diseases, and preterm labour. Thus, useful markers of systemic exposure to periodontitis are needed. Markers of periodontitis in serum include those derived directly from periodontopathic pathogens and those originating from the host defence and immune mechanisms. Periodontitis is associated with endotoxemia, which can be directly measured as elevated concentrations of lipopolysaccharide (LPS) in periodontitis patients compared with healthy subjects. Also indirect methods determining endotoxemia, such as elevated concentrations of serum LPS binding protein, soluble CD14, and antibodies to LPS of periodontal pathogens have been reported. Surrogate measures of the host response against periodontal infection, such as matrix metalloproteinases, cytokines, chemokines, inflammation markers, antiphospholipid antibodies, and antibodies to periodontal pathogens, have been used. Of these, however, only antibodies to periodontal pathogens may be seen as specific markers of systemic exposure to periodontopathic pathogens. In this paper we describe and discuss serum markers of periodontitis that have been used for research purposes and/or to support diagnostics. Based on literature review, we encourage research and development of serum screening methods for periodontitis that could be used by general physicians.

The identification and exploration of new drug candidates to fight diseases is a major imperative for improving human health. The traditional mechanism utilised to identify new compounds with therapeutic potential has been to systematically analyse large libraries of small molecules for lead compounds with a desired bioactivity in protein or cell based assays. Identified lead compounds were subsequently assessed for their potential as lead drugs. In the last few years, small molecule screens were also carried out in vivo, on whole organisms such as the zebrafish. Cost efficient maintenance together with abundant manipulatory techniques and molecular tools have made the zebrafish a preferred system in which to perform large-scale screens. Numerous studies have revealed that zebrafish mutants can accurately model many aspects of human diseases. Therefore, small molecules identified in zebrafish-based screens can be particularly valuable in identifying lead compounds with direct therapeutic relevance to specific human disease states. Here, we review the role of zebrafish-based screens in the emerging field of chemical genetics.