oa Editorial [Hot Topic:Therapeutic Potential of Peptide Motifs - Part V (Executive Guest Editor: Jean-Claude Herve)]

The production of new molecular entities endowed with salutary medicinal properties is a formidable challenge; synthetic molecules that can bind with high sequence specificity to a chosen target in a protein or gene sequence are of major interest in medicinal and biotechnological contexts. The general awareness of the importance of peptides in physiology and pathophysiology has markedly increased over the last few years. With the advancements in the analysis of whole genomes, the knowledge base in gene sequence and expression data useful for protein and peptide analysis has drastically increased. The medical need for relevant biomarkers is enormous. Peptides have a number of advantages over small molecules in terms of specificity and affinity for targets, and over antibodies in terms of size. Novel therapeutic peptides currently derived from active pre-existing peptides or from high-throughput screening and are optimized following a rational drug design approach. Molecules of interest have to prove their ability to influence the disease outcome in animal models and must respond to a set of criteria based on toxicity studies, ease of administration, cost of their synthesis and logistic for clinical use to validate it; as a good candidate in a therapeutic perspective. Peptides can indeed be regarded as ideal agents (as “magic bullets”) for diagnostic and therapeutic applications because of their fast clearance, rapid tissue penetration, and low antigenicity, and also of their easy production, allowing innumerable biological applications. They can easily be engineered to improve their biological activities as well as their stability and their efficient delivery to specific targets. This fifth themed issue of Current Pharmaceutical Design, for which I have the honor to be the Executive Guest Editor, addresses topical issues to some of these potential utilizations of peptide motifs for a variety of genetic and acquired diseases. Alzheimer's disease, the most common form of age-related neurodegenerative disorder, is characterized by the presence of extracellular senile plaques, neurofibrillary tangles and neuronal loss in the brain. Senile plaques are composed of aggregations of small peptides called amyloid β (Aβ). Aβ is produced during normal cell metabolism through proteolytic processing of the amyloid precursor protein, expressed constitutively by many cell types throughout life. Recent studies have shown that Aβ is neurotoxic and that this neurotoxicity is related to its aggregation state into insoluble β-sheet fibrils. Erik Portelius, Niklas Mattsson, Ulf Andreasson, Kaj Blennow and Henrik Zetterberg [1] present an overview of the many aspects of Aβ and its isoforms with special focus on their potential role as diagnostic and theragnostic markers. The major constituent of neurofibrillary tangles is Tau, a microtubule-associated protein, whose increased hyperphosphorylation is known to cause memory impairments. In the amyloid cascade hypothesis, toxic concentrations of Aβ would trigger changes in Tau and consequent neurofibrillary tangle formation. Natalia Shiryaev, Regina Pickman, Eliezer Giladi, and Illana Gozes [2] examine the protecting effects of chronic daily administration of short peptide snippets against deficits in spatial memory and the underlying tauopathy. Endothelins (ETs) are peptides produced primarily in the endothelium and playing a key role in vascular homeostasis. The ET system consists of three ET isoforms (ET-1, -2 and -3) and two G-protein-coupled receptors, ET(A) and ET(B). In the cardiovascular system, ETs, particularly ET-1, are expressed in smooth muscle cells, cardiomyocytes, fibroblasts, and notably in vascular endothelial cells, and many of the cardiovascular complications associated with aging and cardiovascular risk factors (including e.g. hypertension, atherosclerosis or fibrosis) appear initially attributable, at least in part, to endothelial dysfunction. Martin Houde, Julie Labonté and Pedro D'Orléans-Juste [3] summarize the knowledge to date and future perspectives related to the use of peptide antagonists targeting endothelin receptors in physiological and pathological settings. Neuropeptides are peptides released by neurons to communicate with each other by acting on cell surface receptors, particularly G protein-coupled receptors (GPCRs) to control a wide spectrum of physiological functions. Genomic sequencing efforts have yielded a large number of cDNA sequences that potentially encode novel candidate peptide precursors, as well as hundreds of GPCRs with no known cognate ligands, termed “orphan GPCRs”, that became the roots of reverse pharmacology, in which receptors are attempted to be matched to potential transmitters. Yan Zhang, Zhiwei Wang, Gregory Scott Parks and Olivier Civelli [4] retrace the history of the orphan GPCRs and the discoveries of their endogenous ligands and discuss the difficulties that the search for new ligands is presently encountering and the challenges facing neuropeptide discovery....