Mini Reviews in Medicinal Chemistry - Volume 9, Issue 2, 2009

Heat shock protein 90 has emerged as a promising target for the treatment of cancer and neurodegenerative diseases. This review summarizes recent advancements towards the development of natural products as they pertain to the biological and chemical understanding of this molecular chaperone.

The importance of neutrophils in human disease such as rheumatoid arthritis, asthma, adult respiratory distress syndrome, and COPD has prompted the search for drugs capable to slow down neutrophil-dependent inflammation, without interference with innate immune responses. In this review, we summarize new potential drugs targets against neutrophils mediated inflammatory responses.

Solid- phase synthesis is an approach, where synthetic transformation in carbohydrates are carried out with one of the reactant molecule attached to an insoluble material referred as polymeric support via linker. In recent years, it has been extensively accepted as fast and accurate method for the synthesis of biologically active oligosaccharides. This review attempts to focus on various methods of oligosaccharide synthesis by solid- phase including their applications.

Multidrug resistance (MDR) is a limitation to cancer chemotherapy, antibiotic treatment and HIV medication. Molecular models of the ABC transporters ABCB1 (P-glycoprotein), ABCC4 (multidrug resistance protein 4 (MRP4)) and ABCC5 (MRP5), which are involved in MDR, may aid in the development of drugs inhibiting anticancer agents efflux.

Drug-resistant bacteria are now a global health threat. In the last 5 years the WHO, The House of Lords (UK), the Centre for Disease Control (USA) and many more agencies have presented reports on the scale of this problem. Microorganisms multiply very rapidly and have adapted to fill almost every available environmental niche (Rapidly growing species of bacteria under ideal conditions of growth can multiply in about 20 minutes). All members of the chemically related β-lactam class act at the same phase in cell wall synthesis; as a result, a bacterial cell resistant to one agent is often resistant to all other analogues. The beta-peptide has two promising characteristics that distinguish it from traditional antibiotics. Firstly, bacteria may have trouble developing resistance to the beta-peptide since bacterial defenses may not recognize its unnatural amino acids. Secondly, the magainins that the beta-peptides mimic have been around for millions of years, yet bacteria have not become resistant to them. All classes of antibiotics are subject to resistance by an efflux mechanism mediated by more than one type of pump within the same organism. The bacterial cell may have a membrane pump capable of pumping a class or several classes of antibacterial agents back out of the cell. Other mechanisms of drug resistance include destruction of beta-lactam ring by β-lactamases, impermeability of the drug into the bacterial cell wall, alteration of targets within the bacterial cells and the by-pass mechanism (bacterial cell may have acquired an alternative mechanism for achieving the essential function).

Malaria, perhaps one of the most serious and widespread diseases encountered by mankind, continues to be a major threat to about 40 % of the world's population, especially in the developing world. As malaria vaccines remain problematic, chemotherapy still is the most important weapon in the fight against the disease. However, almost all available drugs have been compromised by the highly adaptable parasite, and the increasing drug resistance of Plasmodium falciparum continues to be the main problem. Therefore, the limited clinical repertoire of effective drugs and the emergence of multi-resistant strains substantiate the need for new anti-malarials. Plant-derived artemisinin is currently the only available drug that is globally effective, but alarmingly, recent studies suggest that resistance already may be developing. Nevertheless, the success story of artemisinin from the herb Qing Hao (Artemisia annua L.), used as a remedy in traditional Chinese medicine for more than two thousand years, shows once again that natural products serve as an invaluable reservoir of lead compounds for sophisticated small molecules. This review outlines the major anti-malarials, summarizing recent knowledge about their mode of action and the development of drug resistance. Furthermore, the most promising and recently discovered natural products with anti-malarial potential will be introduced.

Many biologically active peptides are protected from general proteolytic degradation by evolutionary conserved prolines (Pro), due to conformational constraints imposed by the Pro residue. Thus the biological importance of prolyl-specific peptidases points to a high potential for drug discovery for this family of enzymes. Panels of inhibitors have been synthesized and their effects, determined in biological models, suggest the inhibition of families of enzymes with similar activities. Prolyl-specific aminodipeptidases include dipeptidyl-aminodipeptidase IV (DPP IV)/CD26, DPP8, DPP9 and fibroblast activation protease-α (FAP-α)/seprase, able to release X-Pro dipeptides from the N-terminus of peptides. DPP IV inhibitors are in clinical use for type 2 diabetes. In this review, the expression and the potential functions of prolyl-aminodipeptidases are reviewed in diseases, and the inhibitors developed for these enzymes are discussed, with a specific focus on inhibitors able to discriminate between DPP IV and fibroblast activation protease-α (FAPα)/seprase as potential leads for the treatment of fibrogenic diseases.

The diagnosis and assessment of brain damage is currently based on the clinical examination and the modern neuro-imaging techniques. Electrophysiology, haemodynamic monitoring and invasive neuromonitoring constitute additional tools for monitoring of the brain function and clinical course of the patient. However, despite the substantial progress, clinical and neuro-monitoring methods are quite often not sufficient to evaluate and quantify the severity of the initial and secondary destructive processes and hence they cannot guide efficient therapeutic measures and prognosticate effectively the outcome. During the last decades, researchers and clinicians have focused on specific markers of brain cell damage to improve the diagnosis and monitoring of neurological insults. Lactate dehydrogenase, creatine kinase, neuron specific enolase, have been proposed as potential markers of brain injury. More recently, other glial markers such as the Myelin Basic Protein, the glial fibrillary acidic protein and the S-100B protein have been measured in blood and used as surrogate biochemical markers for brain injury. This review summarizes published findings on the above brain specific serum biochemical markers with emphasis on those with clinical utility.

Small RNAs have shown to be ubiquitous, useful, post-transcriptional gene silencers in a diverse array of living organisms. As a result of homologous sequence interactions, these small RNAs repress gene expression. Through a process called RNA interference (RNAi), double strand RNA molecules are processed by an enzyme called Dicer, which cleaves RNA duplexes into 21-23 base pair oligomers. Depending on their end-point functions, these oligomers are named differently, the two most common being small interfering RNAs (siRNAs) and microRNAs (miRNAs). These small RNAs are the effector molecules for inducing RNAi, leading to post-transcriptional gene silencing by guiding the RNAiinduced silencing complex (RISC) to the target mRNA. By exploiting these small RNAs, it is possible to regulate the expression of genes related to human disease. The knockdown of such target genes can be achieved by transfecting cells with synthetically engineered small RNAs or small RNA expressing vectors. Within recent years, studies have also shown the important role of miRNAs in different diseases. By using several chemically engineered anti-miRNA oligonucleotides, disease related miRNAs can be specifically and effectively silenced. Since RNAi has developed into an everyday method for in vitro knockdown of any target gene of interest, the next step is to further explore its potential in vivo and the unique opportunities it holds for the development of novel therapeutic strategies. This review explores the various applications of small RNA technology in in vivo studies, and its potential for silencing genes associated with various human diseases. We describe the latest development in small RNA technology for both gene knockdown, and the inhibition of translational silencing in animal studies. A variety of small RNA formulations and modifications will be reviewed for their improvement on stability and half-life, their safety and off-target effects, and their efficiency and specificity of gene silencing.

Recent evidence suggests that antiglucocorticoids, like conventional antidepressants, may recover depressive symptoms by boosting hippocampal neurogenesis. Here, we explore several possible antiglucocorticoid-based antidepressive therapeutic strategies. Firstly, we review specific glucocorticoid receptor/antagonist interactions. Secondly, we discuss a potential new therapeutic target, doublecortin-like kinase, which regulates glucocorticoid signaling in neuronal progenitor cells.

Burkholderia pseudomallei is the causative agent of melioidosis, a fatal disease that is endemic to Southeast Asia and northern Australia. The clinical manifestations of melioidosis may range from an acute pneumonia or acute septicemia, to chronic and latent infections. B. pseudomallei is inherently resistant to a number of antibiotics, and even with aggressive antibiotic therapy, the mortality rate remains high, and the incidence of relapse is common. The resistance of this organism to a number of antibiotics has created a need for the development of other therapeutic strategies, including the identification of novel therapeutic targets. B. pseudomallei has been shown to produce a number of capsular polysaccharides, one of which has been shown to contribute to the virulence of the organism. The structures of these polysaccharides have been determined and the genes encoding for the biosynthesis of one of the capsular polysaccharides (CPS I) have been identified. Analysis of the genome sequence of this organism has revealed the presence of three other capsule gene clusters that may encode for the chemical structures previously identified. Since one of the capsules produced by B. pseudomallei has been shown to be important in virulence, the genes encoding for the proteins responsible for its biosynthesis may be considered as potential targets.

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