Current Medicinal Chemistry - Volume 15, Issue 27, 2008

West Nile Virus (WNV) has spread rapidly during the last decade across five continents causing disease and fatalities in humans and mammals. It highlights the serious threat to both our health and the economy posed by viruses crossing species, in this case from migratory birds via mosquitoes to mammals. There is no vaccine or antiviral drug for treating WNV infection. One attractive target for antiviral development is a viral trypsin-like serine protease, encoded by the N-terminal 184 amino acids of NS3, which is only active when tethered to its cofactor, NS2B. This protease, NS2B/NS3pro, cleaves the viral polyprotein to release structural and non-structural viral proteins that are essential in viral replication and assembly of new virus particles. Disruption of this protease activity is lethal for virus replication. The NS3 protein also has other enzymes within its sequence (helicase, nucleoside triphosphatase, RNA triphosphatase), all of which are tightly regulated through localisation within membranous compartments in the infected cell. This review describes the various roles of NS3, focussing on NS2B-NS3 protease and its function and regulation in WNV replication and infection. Current advances towards development of antiviral inhibitors of NS2B/NS3pro are examined along with obstacles to their development as an antiviral therapy.

Currently, breast cancer is considered as one of the leading causes for death in women in the United States. Consumption of natural products has received considerable attention in recent years as a possible approach for cancer prevention in general population. There are numerous cancer preventive agents present in the natural products, which may contribute to their chemopreventive properties. During the past two decades, numerous chemopreventive agents have been isolated and/or synthesized and evaluated for their efficacy in a variety of biological assays. To this end, we have established and utilized mouse mammary gland organ culture model (MMOC) as a bioassay for identifying chemopreventive agents. Mammary glands respond to growth promoting hormones and the physiological differentiation can be reproduced in MMOC in chemically defined medium by altering hormonal milieu. Both estrogen and progesterone dependent (mammary ductal lesions, MDL) and independent (mammary alveolar lesions, MAL) precancerous lesions can be induced in response to a 24 hour exposure to DMBA in MMOC. Suppression of the incidence and multiplicity of these lesions by a possible chemopreventive agent can serve as a tool to evaluate efficacy of potential experimental agents. Using this approach, we have evaluated more than 200 synthetic and natural product-derived chemopreventive agents in this model as a part of the National Cancer Institute-supported projects. Many of these chemopreventive agents expressing significant activity have progressed to the in vivo experimental mammary carcinogenesis studies. Thus, this bioassay has proven to be a valuable tool for screening cancer chemopreventive agents for breast cancer prevention and for understanding molecular mechanism(s) of action of these agents. In this comprehensive review, we provide a complete list of chemopreventive agents evaluated for the efficacy against development of mammary alveolar lesions (MAL) in MMOC along with the recent developments in this area. The structure-activity relationships for many chemopreventive agents evaluated in the MMOC model have been discussed.

Polyethylenimine (PEI), an organic branched or linear polyamine polymer, has been successfully used in the past for DNA complexation and transfection in vitro and in vivo into several cell lines and tissues. PEI was also applied in different fields from gene therapy and several studies have emphasized the importance of this polymer in medicinal chemistry. In this brief critical review the uses and applications of this versatile polymeric molecule will be discussed.

Histone deacetylases (HDACs) and Histone acetyltransferases (HATs) are two kinds of enzymes, which can, by reversible deacetylation and acetylation, modify the structure and function of chromatin histones that are involved in the regulation of gene expression, as well as many non-histone proteins that regulate cell function in eukaryotes. Compared with HATs, HDACs have attracted more and more attentions for two main reasons over the past few years. First, the relationship of HDACs and cancer, as well as several other diseases has been confirmed. Second, many HDAC inhibitors (HDACi) have entered pre-clinical or clinical research as anti-cancer agents and shown satisfying effects. HDACs, including 18 members at least, are subdivided into 4 classes that generally have high structure similarity and related substrate specificity within classes, but have divergent sequence and different functions even between within classes. This review will introduce the relationship between HDACs and cancer along with the enzymes' structure and main function.

APN is an important zinc dependent metallo-exopeptidase; it has been considered as a suitable target for anticancer drug design. In this review we focus on the most effective and the most promising inhibitors of aminopeptidase N. Their binding modes to the enzyme, the attempt to explain the origin of the inhibitory activity, as well as the structure - activity relationship for some of these compounds are discussed. Besides, the structural and electronic requirements of the enzyme active site and the binding pockets, together with the specificity towards the ligands are presented.

Physical insults including but not limited to nerve damage, inflammation, visceral pathologies and cancer generate long lasting pain commonly referred as chronic pain. Recently, members of the chemokine family and their receptors emerged as key modulators in nociceptive influx transmission in neuropathic and inflammatory chronic pain models. To this day, rodents defective in specific chemokine receptors have provided evidence of the implication of chemokine in pain sensitivity. In addition, up-regulation of chemokines and their receptors at multiple levels in the central nervous (CNS) and peripheral (PNS) systems is associated in the development of chronic pain. Indeed, we point out the fact that chemokines are synthesized and released by both neuronal and non-neuronal cells and act as neuromodulators. Even if their functional roles in the CNS remain largely unknown, chemokines participate in the glial activation and modulation of neuronal excitability as well as neurotransmitter release. This review focuses on three chemokines (i.e. CCL2, CXCL12, CX3CL1) recently identified as important mediators of the initiation and maintenance of pain hypersensitivity, thus broadening the panel of new strategies for the management of chronic pain.

Rho-kinase is an effector molecule of RhoA, a monomeric GTP-binding protein, and causes Ca2+ sensitization via inactivation of myosin phosphatase. The major physiological functions of Rho-kinase include contraction, migration, and proliferation in cells. These actions are thought to be related to the pathophysiological features of asthma, i.e., airflow limitation, airway hyperresponsiveness, β-adrenergic desensitization, eosinophil recruitment and airway remodeling. Here, the roles of RhoA/Rho-kinase in the pathophysiology and treatment of asthma were investigated. In airway smooth muscle, pre-exposure to chemical mediators released from inflammatory cells markedly enhances methacholine-induced contraction without elevating intracellular concentrations of Ca2+. This augmented responsiveness to methacholine involves the phosphorylation of myosin phosphatase targeting protein 1 (MYPT1) via Rho-kinase, however, it is attenuated by pre-treatment with Rho-kinase inhibitors such as Y-27632 and HA-1077. Airway smooth muscle contraction due to asthma-related substances such as contractile agonists and reactive oxygen species is suppressed by these Rho-kinase inhibitors. Reduced responsiveness to β-adrenergic receptor agonists occurs via Ca2+ sensitization, after exposure to lysophospholipids and proteases released from inflammatory cells. This β-adrenergic desensitization is also attenuated in the presence of Y-27632. Furthermore, the proliferation of airway smooth muscle cells is elevated by Rho-kinase, however, it is markedly suppressed by Y-27632. Antigen challenges cause hyperresponsiveness and eosinophilia in the airways; however, these reactions are markedly suppressed by these Rho-kinase inhibitors. These findings indicate that RhoA/Rhokinase is involved in the pathophysiology of asthma, and suggest that Rho-kinase inhibitors have therapeutic potential for prohibiting these features. In conclusion, RhoA/Rho-kinase is a novel target molecule for the treatment of asthma.

Artemisinin the sesquiterpene endoperoxide lactone extracted from the herb Artemisia annua, remains the basis for the current preferred treatment against the malaria parasite Plasmodium falciparum. In addition, artemisinin and its derivatives show additional anti-parasite, anti-cancer, and anti-viral properties. Widespread use of this valuable secondary metabolite has been hampered by low production in vivo and high cost of chemical synthesis in vitro. Novel production methods are required to accommodate the ever-growing need for this important drug. Past work has focused on increasing production through traditional breeding approaches, with limited success, and on engineering cultured plants for high production in bioreactors. New research is focusing on heterologous expression systems for this unique biochemical pathway. Recently discovered genes, including a cytochrome P450 and its associated reductase, have been shown to catalyze multiple steps in the biochemical pathway leading to artemisinin. This has the potential to make a semi-synthetic approach to production both possible and cost effective. Artemisinin precursor production in engineered Saccharomyces cerevisiae is about two orders of magnitude higher than from field-grown A. annua. Efforts to increase flux through engineered pathways are on-going in both E. coli and S. cerevisiae through combinations of engineering precursor pathways and downstream optimization of gene expression. This review will compare older approaches to overproduction of this important drug, and then focus on the results from the newer approaches using heterologous expression systems and how they might meet the demands for treating malaria and other diseases.