Current Drug Targets - Volume 16, Issue 7, 2015

Angiogenesis is one of the hallmarks of cancer, including brain tumors. The vascular endothelial growth factor (VEGF) family and their receptors are of utmost importance in the complex interaction between pro- and anti-angiogenic factors, and have a crucial role in tumor angiogenesis. Up to date, targeting the VEGF pathway with specific drugs has yielded interesting results in oncology. In particular bevacizumab (Bev), a humanized monoclonal antibody against VEGF-A, has been approved by the Food and Drug Administration (FDA) for use in recurrent glioblastomas failing standard radiochemotherapy. Bevacizumab is now being extensively investigated in several non-glial brain tumors, such as vestibular schwannomas, meningiomas, ependymomas, medulloblastomas and miscellaneous histotypes. The aim of this review is to reevaluate the literature on the use of Bev in non-glial brain tumors.

On account of the ever increasing resistance of M.tuberculosis strains to orthodox therapy regimens, the task of combating tuberculosis becomes even more challenging. Therefore, there arises a need to isolate new drug targets and subsequently design specific inhibitors for the same. In bacteria, algae, plants and fungi, the synthesis of Branched Chain Amino Acids (BCAAs) is catalyzed by Acetohydroxyacid Synthases (AHAS) group of enzymes. Bacterial AHAS (EC 2.2.1.6) catalyzes the biosynthesis of isoleucine, leucine and valine by utilizing cofactors like Thiamin Diphosphate (ThDP), Flavin Adenine Dinucleotide (FAD) and a divalent metal cation (Usually Mg2+). The anabolic form of the enzyme which is presently under discussion consists of two subunits out of which one is catalytic while the other is regulatory in nature. The product of this enzyme catalyzed reaction is either 2-acetolactate or 2-aceto-2-hydroxybutyrate obtained from self-condensation of pyruvate or condensation of puruvate and 2-ketobutyrate, respectively. These are further converted to the BCAAs by a series of other enzymes. The step catalyzed by AHAS is the first in the entire cascade and hence can be selectively targeted for the inhibition of this pathway. M.tuberculosis AHAS, which is encoded by the ilvB and ilvN operons is structurally related to E.coli AHAS and has a similar function. Therefore, specific drugs belonging to the classes of sulfonylureas, imidazolinones and benzoyl esters can be used as inhibitors of M.tuberculosis AHAS which would consequently deplete the BCAA supply to the bacteria. Thus, efficient bacteriostasis can be achieved.

Human proteins are subjected to more than 200 known post-translational modifications (PTMs) (e.g., phosphorylation, glycosylation, ubiquitination, S-nitrosylation, methylation, Nacetylation, and citrullination) and these PTMs can alter protein structure and function with consequent effects on the multitude of pathways necessary for maintaining the physiological homeostasis. When dysregulated, however, the enzymes that catalyze these PTMs can impact the genesis of countless diseases. In this review, we will focus on protein citrullination, a PTM catalyzed by the Protein Arginine Deiminase (PAD) family of enzymes. Specifically, we will describe the roles of the PADs in both normal human physiology and disease. The development of PAD inhibitors and their efficacy in a variety of autoimmune disorders and cancer will also be discussed.

Cancer has been cursed for human beings for long time. Millions people lost their lives due to cancer. Despite of the several anticancer drugs available, cancer cannot be cured; especially at the late stages without showing any side effect. Heterocyclic compounds exhibit exciting medicinal properties including anticancer. Some market selling heterocyclic anticancer drugs include 5-flourouracil, methortrexate, doxorubicin, daunorubicin, etc. Besides, some natural products such as vinblastine and vincristine are also used as anticancer drugs. Overall, heterocyclic moeities have always been core parts in the expansion of anticancer drugs. This article describes the importance of heterocyclic nuclei in the development of anticancer drugs. Besides, the attempts have been made to discuss both naturally occurring and synthetic heterocyclic compounds as anticancer agents. In addition, some market selling anticancer heterocyclic compounds have been described. Moreover, the efforts have been made to discuss the mechanisms of actions and recent advances in heterocyclic compounds as anticancer agents. The current challenges and future prospectives of heterocyclic compounds have also been discussed. Finally, the suggestions for syntheses of effective, selective, fast and human friendly anticancer agents are discussed into the different sections.

GABAA receptors containing the α5 subunit (α5GABAARs) are found mainly in the hippocampus where they mediate a tonic chloride leak current and contribute a slow component to GABAergic inhibitory synaptic currents. Their inhibitory effect on the excitability of hippocampal neurons at least partly explains why changes in the level of activity of α5GABAARs affect cognition, learning and memory. These receptors have been implicated as potential therapeutic targets for a range of clinical conditions including age-related dementia, stroke, schizophrenia, Down syndrome and anesthetic- induced amnesia. Accordingly, a range of pharmacological modulators that selectively target α5GABAARs, as either inhibitors or allosteric enhancers, have been developed. Although many of these compounds show therapeutic effects in animal models of the above clinical disorders, none has been marketed yet due to unsuccessful clinical trials and toxicity in humans. These experiments have also revealed paradoxical effects of α5GABAAR modulation (e.g., cognitive impairments can be reversed by both positive and negative modulation), suggesting that our knowledge of the physiological roles of α5GABAARs is incomplete. This review highlights the various positive and negative modulators for α5GABAARs that have been developed, key findings concerning their effects in behavioral studies, and their importance across a number of therapeutic fields. It also highlights some of the gaps in our knowledge of the physiological and pathological roles of α5GABAARs.

3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) are potent cholesterol- lowering drugs which also possess beneficial antioxidant, antiinflammatory, immunomodulatory, and antiexcitotoxic effects. In addition, statins have proven neuroprotective effects in several neurological diseases: stroke, cerebral ischemia, Alzheimer’s and Parkinson’s disease, multiple sclerosis and traumatic brain injury. Relatively few studies have investigated the potential anti-seizure properties of statins in epilepsy and the possible underlying protective mechanisms that may be involved. This review summarizes the currently available data concerning statin effects in modulating seizure activity (sometimes adversely) and epileptogenesis in different experimental models as well as in clinical studies. Furthermore, we analyze the consequences of some of the more commonly reported statin–anticonvulsant drug interactions in the literature, discuss some of the adverse effects of statins encountered in clinical practice and comment on the potential future usefulness of statins in epilepsy therapy.

A major breakthrough in understanding the steps and signalling that drives the HCV to reach a full life-cycle has been achieved by in vitro models that have facilitated elevated virus production, resulting in the discovery of pathways and factors involved in virus entry, translation and replication. The HCV enters host cells through binding of its envelope glycoproteins to cell receptors, followed by clathrin-mediated endocytosis and fusion with cell membranes, leading to virus uncoating and cell entry. This chain of events is mediated by sequential involvement of different co-receptors, for example, SR-B1, CD81 and the tight-junction proteins- claudin and occludin. HCV RNA replication and translation are coupled processes, requiring cooperation of replicase, helicase and other viral proteins with cell-regulatory factors. Virion packaging and release are highly targetable steps, although they require greater in-depth investigation. The HCV-immune response appears to be fairly ineffective, and neutralizing antibodies that inhibit E2-CD81 binding are unable to resolve infection. HCV-transmission through cell-to-cell contact has been implicated in the evolution of chronic infection. In particular, CD81-dependency and the role of other co-factors involved in entry in cell-to-cell infection, as well as virus escape from host-neutralization still require confirmation. To highlight viral and cell mechanisms implicated in HCVinfection, we review here some of the major discoveries that have been made, from virus entry to its release from infected cells, in understanding the HCV host-cell interplay, which may help in defining new molecular targets to provide therapeutic antiviral strategies.

Besides being an important source of fuel and structural components of biological membranes, free fatty acids (FFAs) are known to display a wide variety of roles that include modulation of receptor signaling and regulation of gene expression among many. FFAs play a significant role in maintaining metabolic homeostasis by activating specific G-Protein Coupled Receptors (GPCRs) in pancreatic β cells, immune cells, white adipose tissue, intestine and several other tissues. Free Fatty acid receptor 2 (FFAR2) also known as GPR43 belongs to this group of GPCRs and has been shown to participate in a number of important biological activities. FFAR2 is activated by short-chain fatty acids (SCFAs) such as acetate, propionate and butyrate. SCFAs are formed in the distal gut by bacterial fermentation of macro-fibrous material that escapes digestion in the upper gastrointestinal tract and enters the colon and have been shown to play vital role in the immune regulation and metabolic homeostasis. FFAR2 and other free fatty acid receptors are considered key components of the body’s nutrient sensing mechanism and targeting these receptors is assumed to offer novel therapies for the management of diabetes and other metabolic disorders. This review aims to summarize the current state of our understanding of FFAR2 biology with a particular focus on its role in metabolic homeostasis.