Current Medicinal Chemistry - Volume 18, Issue 36, 2011

Excitatory neurotransmission mediated by NMDA (N-methyl-D-aspartic acid) receptors plays a key role in both healthy and diseased processes in the brain. Therefore, bioactive compounds that can interact selectively with these receptors have been the aim of extensive research in the search of effective therapeutic agents or, at least, useful pharmacological tools. NMDA receptors are heteromeric ion channels that contain different modulatory sites capable to bind subunit-selective ligands. In particular, the activation of NMDA receptors requires two distinct ligands: glutamate (the endogenous agonist) and glycine (the co-agonist). In view of the renewed interest in this research area and the high therapeutic potential of this target, this review presents an updated survey of ligands which interact with the glutamate binding-site of the NMDA receptors, their rational development, and data on the structure-activity relationship which are of utmost importance for the design of novel lead compounds.

Cancer has long been considered a disease that is associated with immune tolerance. Its connection with inflammation initially appears paradoxical. During the last decade, it has become increasingly clear that immune infiltrates form an integral part of tumor and critically contribute to its development and progression. In the tumor milieu, a variety of inflammatory mediators, such as cytokines (IL- 6, IL-10, VEGF, TGFβ, M-CSF and GM-CSF), chemokines (CCL20 and CXCL8), hormones (prostanoids like PGE2), reactive oxygen species and cellular constituents (gangliosides), are continuously produced. These mediators represent a critical interface between immune and neoplastic compartments. Not only do they continuously support tumor survival and expansion, but suppress the function of immune cells, notably, dendritic cells - the powerful antigen presenting cells that are crucial for induction of tumor-specific immune responses. This review summarizes such a dual role of inflammatory factors and discusses the controversies associated with specific mediators including IL-10, GM-CSF and ROS in tumor and immune modulation. Identifying the inflammatory signature of cancer patients hence represents a critical task for individualized immunotherapy in the future.

At the first glance the vertebrate body appears to be symmetric, however, left and right sides are different. This is tightly controlled during embryonic development, and may as well affect the spatial occurrence of diseases. In the embryo, determination of the left and right sides takes place before and during gastrulation. Its failure results in heterotaxia, a diverse group of congenital laterality disorders characterized by left-right displacement of organs. In recent years, our knowledge about the molecular control of left-right asymmetry during embryonic development has grown considerably. However, almost nothing is known about the etiology of cancer laterality. Mammary carcinoma is 5 - 10% more likely to arise in the left breast. The left side of the body is also 10% more prone to melanoma development. Whereas the right predominance of lung, ovarian and testicular cancer might be explained by the greater organ mass on that side, possible reasons for left predominance of mammary carcinoma and melanoma are highly speculative. Sleeping behavior, handedness, nursing behavior and asymmetric sun exposure were named. A possible interrelation between the molecular control of left-right asymmetry and cancer has not yet been discussed in detail. Here we present an overview of molecules involved in both processes, focusing on laterality of breast cancer. Several secreted and membrane-bound growth factors such as Nodal, Lefty, FGF, HB-EGF and HGF as well as transcription factors (e.g. Pitx2, FoxA2) may be candidates with such overlapping functions. Studies on cancer laterality in transgenic mice are needed to make progress in this neglected research field.

The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway is a central regulator in cell proliferation, growth, and angiogenesis. Inhibition of this pathway therefore is a major strategy for cancer chemotherapy. In order to induce the maximal therapeutic outcome in cancer treatment, vertical inhibition of the PI3K/AKT/mTOR pathway or horizontal inhibition of PI3K/AKT/mTOR and other kinases has been reported. In this review, we discuss the drug design and clinical development of dual inhibitors of PI3K and mTOR as well as the mTOR-selective inhibitors, classified based on the mechanism of action and the chemical structures. Structural determinants for increasing selectivity toward PI3Kα or mTOR are revealed from the structure-activity relationship of the reported inhibitors. Current clinical development in combination therapy of inhibitors involving in the PI3K/AKT/mTOR pathway is also discussed.

4-phenylbutyrate (PBA) is a small molecule that restores cognitive deficits in animal models of Alzheimer's disease (AD). Although the molecular basis of the cognitive benefits of PBA remains unknown, a multi-modal/multi-target mechanism has been proposed. Putative targets of this drug are different from those of drugs that are now used in clinical trials. As PBA is already administered to patients with congenital defects affecting enzymes in the urea cycle, it can be rapidly tested in AD clinical trials. However, the main drawback to its therapeutic use is the high dosage required (up to 15 g/day). Thus, deciphering the precise mechanism(s) of action of this drug may enable novel drugs with similar therapeutic effects to PBA to be developed that can be used at more manageable doses.

Humanin (HN), a short amino acid peptide, protects neurons as well as other cells from amyloid β-induced toxicities and other stresses. A number of HN binding proteins have been identified and their involvements in HN-mediated neuroprotection have been suggested in some cases. However, the way HN binds to the target molecules has never been clarified. Here we will review the structures of HN and HN analogs in solution as a function of solvent conditions and attempt to relate their structural characteristics to the functional properties.

Hepatitis C virus (HCV) infection has emerged as one of the most significant disease to affect humans. Despite its large medical and economical impact, there are no vaccines or efficient therapies without major side effects. The HCV non-structural protein 5B (NS5B) is the RNA-dependent RNA polymerase responsible for the complete copy of the RNA viral genome and is a target of choice for the development of anti-HCV drugs. Although many small molecules have been identified as allosteric inhibitors of NS5B, very few are active in clinical applications. Developments in the field have prompted us to review the research work on HCV NS5B polymerase inhibitors, especially their structure activity relationships and molecular modeling studies. This review will focus on the journey of drug discovery of HCV NS5B inhibitors covering both nucleoside and non-nucleosides.

Peroxisome-Proliferating Activating Receptors (PPARs) have long been established as validated targets for therapeutic intervention in several important disease states, including type II diabetes and dyslipidemia. More recently, evidence has implicated novel regulatory roles for PPARs in cancer, inflammation and neurodegeneration. Although current PPAR targeting treatments exist, most are associated with undesirable and potentially life-threatening side effects. Consequent from these observations is a significant research effort into PPAR modulator drug discovery and design. In this review, the progress of PPAR modulator design over the past several years will be highlighted. Particular focus on how detailed structural information and virtual screening techniques can aid in the rational design and development of tailored next generation PPAR drug therapeutics will be discussed.

Paraoxonase 1 (PON1) is an enzyme which is mainly synthesized in the liver. PON1 circulates in the blood bound to HDL and delays or prevents the oxidation of LDL. Single nucleotide polymorphisms significantly determine PON1 status in humans. A high PON1 status may be associated with a reduced cardiovascular disease risk. By using in silico databases we suggest various transcription factors and micro RNA as putative regulators of PON1. Furthermore we predict functional partners of PON1 by using a text mining tool. Beside genetic and life style factors PON1 status may be determined by drugs (e.g., statins, fibrates) and dietary factors. Dietary modulators of PON1 status include fat and fatty acids, antioxidant vitamins (e.g. ascorbic acid, tocopherol), polyphenols and polyphenol-rich foods.

It is well known that legumes, especially soybeans, are beneficial to health due to the presence of saponins and an abundance of fiber and proteins. Defensins and other related defense proteins with antifungal activity in legumes act against fungi which are human pathogens and also against phytopathogenic fungi. These proteins exhibit HIV-1 reverse transcriptase inhibitory and antitumor activities. Some of these proteins have remarkable stability to proteases, and changes in pH and temperature and are promising therapeutic candidates.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons which brings to muscular atrophy, paralysis and death in 3-5 years from starting symptoms. In about 10% of cases ALS is familiar and in a relevant percent of these cases, mutations of the enzyme copper-zinc superoxide dismutase 1 (SOD1) are found. Transgenic mice expressing mutated forms of SOD1 replicate with fidelity the onset and progression of the disease and have been largely used to test therapies to be translated to patients in clinical trials. Over years, many therapeutic approaches have been attempted in mice model often with significant, albeit limited, benefits on disease onset, progression and lifespan. Unfortunately almost all the clinical trials based on these preclinical results, have been unsuccessful. In the present review, both results of preclinical and clinical studies are summarized, focusing on the main mechanisms that are believed to contribute to this complex disease: oxidative stress, excitotoxicity, neuroinflammation, mitochondrial dysfunction, errors in protein folding and disposal, lack of trophic factors. Future perspectives related to genetic and stem cell approaches are briefly considered.

Dendritic cells (DCs) are professional antigen presenting cells (APCs) capable of linking innate and adaptive immunity during infection. After recognition of pathogen-associated molecular patterns (PAMPs), DCs can engulf, process and present bacteria-derived antigens on MHC molecules to T cells. Because of the key role that DCs play on the initiation of innate and adaptive immunity, alterations in their function could render the host susceptible to bacterial dissemination. Consistent with this notion, is the observation that several pathogenic bacteria have evolved mechanisms to impair the DC capacity to prime naive T cells. One of such bacteria is Salmonella enterica serovar Typhimurium, which causes a typhoid-like disease in mice and gastroenteritis in humans. Recent studies have shown that virulent Salmonella can use intestinal DCs to spread inside the host, evading T cell priming. The avoidance of T cell recognition by Salmonella is in large part achieved by the activity of gene products encoded on Salmonella Pathogenicity Islands -1 and - 2. The understanding of some of the remarkable molecular virulence mechanisms displayed by Salmonella has contributed to the design of new vaccines capable of inducing protective immunity against this pathogen in mouse models. Here we describe recent data underscoring the virulence mechanisms used by Salmonella to exploit DC function and discuss strategies based on this new knowledge aimed at the design of new efficient and safe vaccines against this pathogen.

In this review, we focus on recent developments in biomaterials of poly(lactic acid)-poly(ethylene oxide)-poly(lactic acid) (PLA-PEO-PLA) triblock copolymers. This system has been widely explored for a number of applications in controlled and sustained release of drugs and in tissue engineering devices. New insights into self-assembly of these materials have resulted in new PLA-PEOPLA solutions and gels with novel structural, mechanical, and drug release properties. Recent innovations include hydrogels with nanoscale crystalline domains, solutions and gels based on PLA stereocomplexes, and nanoparticle-copolymer assemblies. We first briefly review synthetic approaches to these materials. We then describe characterization of the solution properties, formation of micelles, drug release characteristics, and investigation of the sol-gel transition. The properties of PLA-PEO-PLA hydrogels are then discussed, including the effect of crystalline domains on the gel microstructure and efforts to tune the elastic modulus and degredation properties of gels through the addition of chemical crosslinks. In the second half of the review, we discuss the wide variety of biomedical applications currently being pursued for PLA-PEO-PLA triblock copolymer systems. Polymer-nanoparticle complexes have been investigated to facilitate the formation of metal nanoclusters used as biosensors, as well as to enhance the elastic modulus of hydrogels. Thin polymer films have also been investigated for use as tissue engineering scaffolds and as drug-eluding coatings for stents and other medical implants. Finally, we discuss future directions for biomedical applications of this system, including new strategies for improving the specificity and cell affinity of PLA-based biomaterials.

Elucidating the interaction relationship between target proteins and all drugs is critical for the discovery of new drug targets. However, it is a big challenge to integrate and optimize different feature information into one single “knowledge view” for drug-target interaction prediction. In this article, a feature selection method was proposed to rank the original feature sets. Then, an improved bipartite learning graph method was used to predict four types of drug-target datasets based on the optimized feature subsets. The crossvalidation results demonstrate that the proposed method can provide superior performance than previous method on four classes of drug target families.