Current Medicinal Chemistry - Volume 13, Issue 19, 2006

There is a need for novel drugs for the treatment of infectious diseases, autoimmunity and cancer. Cyclic peptides constitute a class of compounds that have made crucial contributions to the treatment of certain diseases. Penicillin, Vancomycin, Cyclosporin, the Echinocandins and Bleomycin are well-known cyclic peptides. Cyclic peptides, compared to linear peptides, have been considered to have greater potential as therapeutic agents due to their increased chemical and enzymatic stability, receptor selectively, and improved pharmacodynamic properties. They have been used as synthetic immunogens, transmembrane ion channels, antigens for Herpes Simplex Virus, potential immunotherapeutic vaccines for diabetes and Experimental Autoimmune Encephalomyelitis - an animal model of Multiple Sclerosis, as inhibitors against α-amylase and as protein stabilizers. Herein, we review important cyclic peptides as therapeutic agents in disease.

Gangliosides are glycolipids that contain sialic acid and they are mainly located on the outer leaflet of the cellular plasma membrane of most vertebrate and some invertebrate cells. Because they have structurally diverse, bulky and negatively charged oligosaccharide moieties, gangliosides endow cell membranes with unique molecular characteristics. Although they are abundant in the central nervous system (CNS), the complete loss of gangliosides in mice does not result in gross morphological abnormalities of the CNS. However, mutant mice develop neurodegenerative diseases and die soon after birth, suggesting that gangliosides are required for the maintenance and development of a stable CNS and are crucial to sustain life. At the cellular level, gangliosides influence cell growth and death, probably because they are involved in the lipid-mediated assembly of signaling molecules such as growth factor receptors or integrins on the membranes. This article addresses the structural similarity between the tandem sialic acid residues of gangliosides and nicotinamide adenine dinucleotide (NAD+) determined from biochemical data showing that gangliosides inhibit NAD+ glycohydrolase activity and theoretical considerations. An essential feature of the structural similarity resides in a negative charge cluster formed by the two carboxyl groups in the tandem sialic acid residues and the diphosphate moiety of NAD+. The potential physiological role(s) of gangliosides on the regulation of extracellular nucleotide metabolism are discussed.

Capsaicin-sensitive sensory neurons are nociceptive neurons that release calcitonin gene-related peptide (CGRP) on activation. Since CGRP has potent vasodilatory activity, it has long been considered to be involved in aggravation of inflammation such as tissue hyperemia and edema. However, since ablation of the sensory fibers can result in a marked increase in the severity of inflammation and reperfusion-induced tissue inflammatory responses are enhanced in congenital CGRP-knockout mice, the sensory neurons have been shown to play a role in the maintenance of tissue integrity by regulating local inflammatory responses. We demonstrated in rodents that stimulation of sensory neurons reduces hypertension, stress-induced gastric mucosal injury, reperfusion-induced liver injury, and endotoxin-induced shock responses by attenuating inflammatory responses such as increases in both tissue levels of tumor necrosis factor (TNF) and tissue accumulation of neutrophils. Attenuation of inflammatory responses by sensory neuron activation can be explained mainly by CGRP-induced increase in the endothelial production of prostacyclin (PGI2). Since inflammatory responses are critically involved in the development of a wide variety of diseases, pharmacological stimulation of sensory neurons might contribute to treatment of various pathologic conditions. In this review, the authors describe molecular mechanism(s) by which sensory neuron activation inhibits TNF production, thereby attenuating inflammatory responses. Furthermore, the authors discuss some clinically useful therapeutic agents that are capable of activating sensory neurons and raise the possibility that pharmacological stimulation of sensory neurons is the new paradigm for future therapeutic strategies.

In order to minimize expensive drug failures it is essential to determine the potential biological activity of new candidates as early as possible. In view of the large libraries of nucleoside analogues that are now being handled in organic synthesis, the identification of a drugs biological activity is advisable even before synthesis and this can be achieved using predictive biological activity methods. In this sense, computer aided rational drug design strategies like Quantitative Structure Activity Relationships (QSAR) or docking approaches have emerged as promising tools. Although a large number of in silico approaches have been described in the literature for the prediction of different biological activities, the use of traditional QSAR applications in the development of new agonist molecules with affinity toward adenosine receptors is scarce. This review attempts to summarize the current level of knowledge concerning computational affinity predictions for adenosine receptors using QSAR models based on knowledge of the agonist ligands. Several computational protocols and different 2D and 3D descriptors have been described in the literature for these targets, but more effort is still required in this area.

Lower airways inflammation is a central feature of many lung diseases, including asthma, chronic obstructive pulmonary disease (COPD) and pneumonia. Although the specific characteristics of the inflammatory responses and the site of inflammation differ between one disease to another, they always involve recruitment and activation of inflammatory cells and changes in structural cells of the lung. Inflammatory responses are associated with an increased expression of a cascade of proteins including cytokines, chemokines, growth factors, enzymes, adhesion molecules and receptors. In most cases the increased expression of these proteins is the result of enhanced gene transcription: many of these genes are not expressed in normal cells under resting conditions but they are induced in the inflammatory process in a cell-specific manner. Transcription factors regulate the expression of many pro-inflammatory genes and play a key role in the pathogenesis of airway inflammation. Many studies have suggested a role for viral infections not only as a causative agent of pneumonia but also of asthma and COPD exacerbations. In this review we will provide an overview of the relationship between common respiratory viral infections and the molecular mechanisms involved in the activation of airway inflammation and on the regulation of transcription factors in these inflammatory respiratory diseases. The relative importance of each transcription factor will be certainly greatly clarified in the next few years with the growing availability of specific inhibitors capable of blocking activation of a specific transcription factor. Clearly this is an exciting new area of ongoing research with promising therapeutic potential.

The incidence of allergic diseases has dramatically increased in recent decades, especially in urban and industrialized areas. It is important socially as well as medically to establish more useful strategies to overcome allergic disorders. Bronchial asthma is a complex disease characterized by airway inflammation involving a Th2-cytokine, interleukin (IL)-13. A substantial body of evidence has accumulated pointing to the pivotal role of IL-13 in the pathogenesis of bronchial asthma, based on mainly analyses of mouse models. In addition to such analyses, the high expression of IL-13 in lesions and genetic association of several genes coding IL-13 signaling molecules with bronchial asthma have raised the possibility that IL-13 plays a pivotal role in the onset or exacerbation of human bronchial asthma. Therefore, IL-13 and its signal pathway are thought to be promising targets to develop a therapeutic agent for bronchial asthma. In this article, we describe how IL-13 is involved in the pathogenesis of bronchial asthma and then how therapeutic agents to block IL-13 signals are developed for bronchial asthma.

A new era in genetics has started 15 years ago, when co-suppression in petunia has been discovered. Later, co-suppression was identified as RNA interference (RNAi) in many plant and lower eukaryote animals. Although an ancient antiviral host defense mechanism in plants, the physiologic role of RNAi in mammals is still not completely understood. RNAi is directed by short interfering RNAs (siRNAs), one subtype of short double stranded RNAs. In this review we summarize the history and mechanisms of RNAi. We also aim to highlight the correlation between structure and efficacy of siRNAs. Delivery is the most important obstacle for siRNA based gene therapy. Viral and nonviral deliveries are discussed. In vivo delivery is the next obstacle to clinical trials with siRNAs. Although hydrodynamic treatment is effective in animals, it cannot be used in human therapy. One possibility is organ selective catheterization. The known side effects of synthesized siRNAs are also discussed. Although there are many problems to face in this new field of gene therapy, successful in vitro and in vivo experiments raise hope for treating human disease with siRNA.

Cathepsin B is an abundant and ubiquitously expressed cysteine peptidase of the papain family. It is involved in many physiological processes, such as remodeling of the extracellular matrix (wound healing), apoptosis, and activation of thyroxine and renin. In addition to its physiological roles, cathepsin B is important in many pathological processes, such as inflammation, parasite infection and cancer, where it is highly up-regulated. In cancer patients, elevated cathepsin B activity correlates to poor therapy outcome. Therefore, it is not surprising that the use of cathepsin B inhibitors reduces both tumor cell motility and invasiveness in vitro. This review summarizes recent developments in cathepsin B inhibition. To date, numerous protein inhibitors of cathepsin B have been described, some of which are of endogenous origin and function as regulators of cathepsin B activity in the cell, such as the cystatins. In addition, some exogenous protein inhibitors of cathepsin B have been isolated from various natural sources, and the use of X-ray crystal structures of cathepsin B complexed with such protein inhibitors has resulted in the design and synthesis of many new small-molecular-weight compounds as inhibitors of cathepsin B. These synthetic compounds generally contain an electrophilic functionality that reacts with cathepsin B. In the present review, these inhibitors are divided according to their mechanisms of action, as reversible and irreversible, and then further subdivided into groups for their full descriptions.

Multiple sclerosis (MS) is a complex neurological disorder characterized by inflammation and degeneration of the central nervous system, primarily involving the white matter. On the basis of a wide body of evidence in experimental models and in affected patients, several attempts to treat MS using drugs which modulate immune reactions have been performed or are currently ongoing. However, it should be stressed that inflammation does not have only a detrimental effect in MS. In fact, parts of the inflammatory events are crucial for the control and conclusion of the acute phase of damage and it is probable that they actually favor regeneration and recovery. Due to the above, several trials with immunosuppressant drugs failed or were suspended because of unexpected worsening of the course of MS. The knowledge of MS immunopathogenesis is so rapidly evolving that any attempt to review it is in some way frustrating. On the other hand, this evolution is at the basis of the several new treatment options which can be hypothesized for this disease. The current status of immunosuppression in MS and the possible future development of MS treatment will be reviewed, with particular reference to those treatments which have already been tested in clinical trials and which are based on sound evidence of a putative interference with specific events occurring in MS, with the sparing of general immunity.