Current Pharmaceutical Design - Volume 18, Issue 6, 2012

During the last decade, scientific and clinical research witnessed a progressive shift from genomics to proteomics. Actually, the genomic era promised much [1] and much has left unfulfilled [2], thus also explaining the rapid development of proteomics and its application to drug discovery at the beginning of this century [3]. Proteomics is giving a significance to genes by providing a direct link to their biological activity. Currently, we are moving a step further, with peptidomics evolving as a functional and effective branch of proteomics [4]. This is because active peptide modules can be exactly designed, easily synthesized and inexpensively produced. Also, peptides have high effectiveness and low toxicity, fast and extensive tissue penetration, and rapid clearance. In essence, peptidomics appears to be the next frontier of scientific research and clinical applications [5]. In this unfolding scenario, the present issue brings together a collection of compelling papers that provide an extensive overview of peptides as novel therapeutic and diagnostic agents. Boyle et al. [6] begin the issue by describing PeptideAtlas, a repository of peptide information with the potential of discovering disease biomarkers; Funke and Willbold [7] discuss peptides developed for diagnosis and therapy of Alzheimer's disease; Seim et al. [8] examine the action of orexigenic and anorexigenic peptide hormones in appetite regulation; Tanabe [9] highlights he possibility of using short peptide modules, such as pentapeptides, for enhancing intestinal barrier function; Lucchese et al. [10] describe the multifold characteristics and potential applications of peptides in oral diseases; Llorens-Cortès et al. [11] focus on the role of apelin on water balance and cardiac functions; Riley et al. [12] summarize the current knowledge on the role of the peptide thymosin beta 4 in cardioprotection and repair; Hancock et al. [13] provide an overview on results achieved to date on the therapeutic potential of host defense peptides in antibiotic-resistant infections; Mocellin [14] gives an overview of peptides derived from melanoma-associated-antigens to be used in anti-melanoma peptide-based vaccines; Kanduc et al. [15] report that a low level of sequence similarity to the host proteins is a common denominator unifying the composite assembly of conformational epitopes already validated in the scientific literature. Overall, the final result is an affresco of the therapeutic potential of peptides in a number of human diseases, such as neurodegenerative pathologies, cardio-vascular disorders, inflammation, and cancer, to name but a few. The contributing Authors are leaders in their respective fields with extensive experience in peptide research. As a guest editor of this issue of Current Pharmaceutical Design, I thank all the Authors for their outstanding contributions. I would also like to thank the Referees who provided critical reviews of the papers. Finally, I wish to thank Dr. William A. Banks, the Editor-in-Chief, and Mr. Kazim Ali Baig for the invitation and support throughout this project.

Mass spectrometry information has long offered the potential of discovering biomarkers that would enable clinicians to diagnose disease, and treat it with targeted therapies. PeptideAtlas currently provides access to large-scale spectra data and identification information. This data, and the generation of targeted peptide information, represents the first step in the process of locating disease biomarkers. Reaching the goal of clinical proteomics requires that this data be integrated with additional information from disease literature and genomic studies. Here we describe PeptideAtlas and associated methods for mining the data, as well as the software tools necessary to support large-scale integration and mining.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with devastating effects. The greatest risk factor to develop AD is age. Today, only symptomatic therapies are available. Additionally, AD can be diagnosed with certainty only post mortem, whereas the diagnosis “probable AD” can be established earliest when severe clinical symptoms appear. Specific neuropathological changes like neurofibrillary tangles and amyloid plaques define AD. Amyloid plaques are mainly composed of the amyloid-βpeptide (Aβ). Several lines of evidence suggest that the progressive concentration and subsequent aggregation and accumulation of Aβplay a fundamental role in the disease progress. Therefore, substances which bind to Aβ and influence aggregation thereof are of great interest. An enormous number of organic substances for therapeutic purposes are described. This review focuses on peptides developed for diagnosis and therapy of AD and discusses the pre- and disadvantages of peptide drugs.

Appetite regulation is highly complex and involves a large number of orexigenic and anorexigenic peptide hormones. These are small, processed, secreted peptides derived from larger prepropeptide precursors. These peptides are important targets for the development of therapeutics for obesity, a global health epidemic. As a case study, we consider the ghrelin axis. The ghrelin axis is likely to be a particularly useful drug target, as it also plays a role in energy homeostasis, adipogenesis, insulin regulation and reward associated with food intake. Ghrelin is the only known circulating gut orexigenic peptide hormone. As it appears to play a role in diet-induced obesity, blocking the action of ghrelin is likely to be effective for treating and preventing obesity. The ghrelin peptide has been targeted using a number of approaches, with ghrelin mirror-image oligonucleotides (Spiegelmers) and immunotherapy showing some promise. The ghrelin receptor, the growth hormone secretagogue receptor, may also provide a useful target and a number of antagonists and inverse agonists have been developed. A particularly promising new target is the enzyme which octanoylates ghrelin, ghrelin O-acyltransferase (GOAT), and drugs that inhibit GOAT are likely to circumvent pharmacological issues associated with approaches that directly target ghrelin or its receptor.

The intestinal epithelial barrier is indispensable to our immune system. Defects in this barrier function have been observed in intestinal disorders such as inflammatory bowel diseases, food allergies, and celiac diseases. Therefore, the modulation of the barrier function is currently viewed as a potentially positive pharmacological outcome. This review describes a unique peptide, Asn-Pro-Trp- Asp-Gln (NPWDQ), which can finely adjust the intestinal barrier. It is obtained by the hydrolysis of casein, a major milk protein, and considerably inhibits the permeation of ovalbumin, one of the food allergens, in Caco-2, a human intestinal cell line. Using DNA microarray, we observed that NPWDQ only up-regulated expression of the occludin gene, whereas the levels of other genes, such as those of the claudin and zonula occludens families, remained unchanged. Increased protein expression of occludin was also observed. The fact that milk-derived peptide(s) can enhance intestinal barrier function gives a new significance to lactation because it plays an important role in promoting the maturation of the intestinal barrier. In this context, it is highly probable and worthy of considerable attention that various bioactive peptides with this type of activity are yet to be observed in the bovine and/or human casein sequence. Moreover, milkderived peptides could be considered as potential candidates for the prevention of certain intestinal disorders.

The oral cavity is home to numerous viruses and micro-organisms recognized as having a role in various oral diseases as well as in infections in other parts of the body. Indeed, in general a microbial infection underlies or is believed to underlie the ample spectrum of oral diseases, from tooth enamel decay to periodontal lesions, from candidiasis to virus-induced oral squamous cell carcinomas, and bullous autoimmune oral disorders. This clinico-pathological context stresses the need of targeted therapies to specifically kill infectious agents in a complex environment such as the oral cavity, and explains the current interest in exploring peptide-based therapeutic approaches in oral and dental research. Here, we review the therapeutic potential of antimicrobial peptides such as LL-37, beta defensins, adrenomedullin, histatins, and of various peptides modulating gene expression and immuno-biological interaction(s) in oral diseases.

The discovery of apelin, an endogenous ligand of the orphan APJ receptor is an important advance for fundamental research and clinical medicine. Apelin and its receptor have a wide tissue distribution not only in the brain but also in peripheral organs including kidney, heart, vessels, and adipose tissue. Apelin is implicated in many physiological and pathophysiological processes such as the regulation of body fluid homeostasis, cardiovascular functions, glucose homeostasis, cell proliferation, and angiogenesis. This review focuses on, i) the various signaling cascades evoked upon stimulation of the apelin receptor by the different molecular forms of apelin found in vivo, ii) the distribution of apelin and its receptor in the brain and the cardiovascular system, iii) the opposing actions of vasopressin and apelin in the regulation of water balance at the central and kidney levels, and on the cardiovascular system regarding regulation of arterial blood pressure, vascular tone, and cardiac function.

Clinical interventions leading to improved survival in patients with acute myocardial infarction have, paradoxically, increased the need for cardiac regenerative strategies as more people are living with heart failure. Over the last 10-15 years there have been significant advances in our understanding of cell-based therapy for cardiac repair. Evidence that paracrine stimulation largely underlies the functional benefits in cell transplantation has led to a paradigm shift in regenerative medicine: from cell therapy to factor/protein-based therapy. Although, future regenerative approaches may likely involve a synergistic protein cocktail, this review will focus on the role of a promising candidate, thymosin beta 4 (Tβ4) in cardioprotection, neovascularization, tissue regeneration and inflammation - all essential components in cardiac repair.

The emergence of infections caused by multi-drug resistant (MDR) pathogens pose a major burden to modern healthcare. Exacerbating this issue is the substantial decline in development of new classes of antibiotics by pharmaceutical companies. This has led to renewed interest in the therapeutic potential of natural anti-infective agents such as host defense peptides (HDPs). The broad antimicrobial and immunomodulatory activities of HDPs and their synthetic derivatives, coupled with the fact that they do not readily induce microbial resistance, makes them extremely valuable leads in the development of new treatment strategies for MDR infections. This review examines our knowledge of the mechanisms behind multi-drug resistance as well as the properties of HDPs and their therapeutic potential, especially in the case of MDR infections. Challenges to their development as new therapeutics are also discussed.

Peptides derived from tumor associated antigens can be utilized to elicit a therapeutically effective immune response against melanoma in experimental models. However, patient vaccination with peptides - although it is often followed by the induction of melanoma- specific T lymphocytes - is rarely associated with tumor response of clinical relevance. In this review I summarize the principles of peptide design as well as the results so far obtained in the clinical setting while treating cutaneous melanoma by means of this active immunotherapy strategy. I also discuss some immunological and methodological issues that might be helpful for the successful development of peptide-based vaccines.

The development of vaccines for new and re-emerging pathologies and infections is based on the ability to define immunogenic epitopes. An immunogenic B-cell peptide epitope is a specific restricted antigen region that is capable of eliciting a humoral immune response and of combining with a specific site on antibodies. Using a number of experimental models and based on data from several literature reports, we identified low levels of sequence similarity to the host proteome as one of the main factors modulating the Bcell epitope repertoire in the humoral immune response. In point of fact, a low level of sequence identity to the host proteins is a common denominator unifying the composite, disparate assembly of linear peptide B-cell epitopes that has been experimentally validated and described in the literature. Here, we explore the proteomic similarity of conformational epitopes experimentally validated and described in published reports. Again, discontinuous epitopic structures formed by non-contiguous amino acid residues were found to define peptide sequences with a low level of similarity to the host. The present meta-analysis adds further significance to the immunological lowsimilarity theory and its clinical implications. Potentially, low-similarity peptide epitopes pave the way for novel effective vaccines in cancer, autoimmunity, and infectious diseases.

Microparticles (MPs) are submicron vesicles (0.1-1 μm) shed from the membrane of platelets, monocytes, endothelial cells and other cell types. Abundant clinical evidence relates increased plasma levels of MPs with several cardiovascular and inflammatory diseases, being a topic of tremendous interest in recent years. MPs have been proposed as potential effectors in thrombosis, inflammation, vascular injury or angiogenesis. Although MPs were traditionally considered noxious actors, recent scientific advances revealed another layer of complexity with their diverse roles in the pathophysiology of thrombotic disorders. Therefore, whilst their impact on the evolution of the disease is indisputable, the milieu of factors regulating MP release is still an intriguing field. Since MPs have been shown to be involved in thrombosis and inflammatory diseases, modulation of their release might have important therapeutic applications and provide further insights into their (patho)physiological roles. In this regard, increasing clinical attention has been devoted to the effects of pharmacological agents on MP circulating levels and antigenic composition. This trend led to many recent studies with special focus on the pharmaceutical options to inhibit formation of procoagulant MPs. Thus, this review aims to summarize available clinical and in vitro literature on mechanisms triggering MP release and modulating their activity.

Aspirin has long been the mainstay of primary and secondary prevention against myocardial infarction and ischemic cerebrovascular events. However, the incremental value of aspirin for primary prevention has recently been subject to debate given data from recent large clinical trials, as the net clinical benefit is small. In secondary prevention, aspirin is still strongly recommended. Efforts in obtaining more efficient antiplatelet agents and to reduce cardiovascular morbidity and mortality have led to the development of new adenosine diphosphate (ADP) receptor antagonists, which are superior to clopidogrel. New generation antiplatelet drugs i.e. prasugrel and ticagrelor aim to reduce atherothrombotic events, mortality and stent thrombosis, as well as overcome low- or non-response to clopidogrel. Further agents with antiplatelet properties are being investigated at present. This overview aims to give insights into the rapidly changing field of antiplatelet strategies in cardiovascular diseases.