Hot topic: Editorial [Therapeutic Potential of Peptide Motifs - Part IV] (Jean Claude Herve)

Jean-Claude      Herve

Abstract

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 progresses 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 fourth themed issue of Current Pharmaceutical Design, for which I have the honour to be Executive Guest Editor, addresses topical issues to some of these potential utilizations of peptide motifs for a variety of genetic and acquired diseases. Cells of multicellular organisms need to communicate and have evolved mechanisms of communication, the most direct and quickest of which is through channels that directly link the cytoplasms of adjacent cells, clustered in specialised plasma membrane domains termed gap junctions and built by docking of two hemichannels (one in each membrane), hexameric torus of junctional proteins (connexins being the most known) around an aqueous pore. The permeability of hemichannels and junctional channels is finely tuned by complex mechanisms that have just begun to be identified. Some peptides may interact with membrane receptors, activating a signalling transduction cascade leading to modifications in the expression of gap junctional proteins or the functional state of channels, some others, that mimic a short sequence of gap junction proteins, may attenuate processes downstream of the putative channel activity and represent very useful tools to investigate the structure of domains of gap junction proteins. Jean Claude Herve and Stefan Dhein [1] present an overview of the literature on peptides targeting gap junction structures. G protein-coupled receptors (GPCRs) or seven-transmembrane domain receptors, present on the surface of all cells, mediate cellular responses to a wide range of extracellular stimuli, as well endogenous chemical signals as exogenous environmental agents (as amino acids, peptides, proteins, amines, lipids, neurotransmitters, hormones, growth factors, odorant molecules, light, etc.). Once activated, GPCRs transduce signals to effectors, enzymes and ion channels. Christian W. Gruber, Markus Muttenthaler and Michael Freissmuth point out how peptides can interfere with GPCR signalling since besides their ligand binding sites (or “orthosteric site”), GPCRs can be targeted at additional sites important to modulate the affinity and efficacy of orthosteric ligands, to regulate G protein signalling or to give rise to G protein-independent signals. The GPCRs with unknown endogenous ligands, called orphan GPCRs, are believed to be the potential targets for drug development, so the task to de-orphanize (identifying the endogenous ligands of) them is actively pursued. Novel neuropeptides acting as GPCR ligands have for example been identified, as orexins, produced by specific subsets of neurons located in the lateral hypothalamic area. L.-C. Chiou, H.-J. Lee, Y.-C. Ho, S.-P. Chen, Y.-Y. Liao, C.-H. Ma, P.-C. Fan, J.-L. Fuh and S.-J. Wang [3] summarize the studies investigating the antinociceptive effects of orexins in various animal models of pain, including trigeminovascular pain, and their cellular mechanisms. Regulation of proteins by reversible phosphorylation is one of the most important modes of regulation of protein functions, the protein switching in most cases between a phosphorylated and an unphosphorylated form, one of these two being an active form while the second is inactive. The phosphorylation state of proteins is controlled by protein kinases, which add a covalently bound phosphate group to proteins, and protein phosphatases, which remove it from phosphoproteins. According to the classification based on structure and substrate specificity, protein tyrosine phosphatases are typically responsible for the dephosphorylation of phosphotyrosine residues. Kui Shen, Lixin Qi and Lynn Stiff [4] discuss the development of the active site-directed protein tyrosine phosphatase inhibitors based on peptides and some closely related non-peptidic scaffolds. Peptide nucleic acids (PNAs) are synthetic DNA analogues in which the sugar phosphate backbone of natural nucleic acid has been replaced with a pseudopeptide chain constituted by N-(2-aminoethyl) glycine monomers, and to which the nucleobases are fixed through a carboxymethyl moiety. This structure gives to PNAs the capacity to hybridize with remarkably high affinity and specificity to complementary nucleic acids, and a great resistance to nucleases and proteinases. Peter E. Nielsen [5] explains how PNA oligomers possess the fundamental properties for gene therapeutic drug discovery exploiting a range of molecular biology/molecular medicine principles and with the possibility of very diverse indications ranging form infections, cancer, and genetic disorders to metabolic diseases. Mitochondria, key regulators of cell life and death, represent a major source of intracellular reactive oxygen species and are particularly vulnerable to oxidative stress. Oxidative damages to mitochondria, impairing mitochondrial function, lead to cell death via apoptosis and necrosis. Mitochondria then play important roles in a wide range of diseases, including cancer, diabetes, cardiovascular disease and age related neurodegenerative diseases. Recent developments in mitochondria-targeted antioxidants have moved closer to providing protection against mitochondrial oxidative damage. The Szeto-Schiller peptide antioxidants represent a novel approach that employs the targeted delivery of antioxidants to the inner mitochondrial membrane. M. Rocha, A. Hernandez-Mijares, K. Garcia-Malpartida, C. Banuls, L. Bellod and V.M. Victor [6] explain how these peptides scavenge hydrogen peroxide and peroxynitrite and inhibit lipid peroxidation to prevent oxidant-induced cell death. Defects in the apoptotic molecular machinery that result in either excessive or insufficient apoptosis are observed in a remarkably wide range of human diseases. Bcl-2 family members regulate the release from the space between the mitochondrial inner and outer membranes of proteins that, once in the cytosol, activate caspase proteases that dismantle cells and signal efficient phagocytosis of cell corpses. Peter E. Czabotar and Guillaume Lessene [7] present recent advances in targeting the Bcl-2 family with both peptides and small molecules to trigger apoptosis in cancer therapy. Vaccines optimize the presentation of an immunogen to the immune system by enhancing or replacing the natural activators of antigen presenting cells in order to promote the delivery and the response of T and B lymphocytes to the immunogen. Peptides can be synthesised with defined chemical modifications to mimic natural epitopes and/or deliberately introduce protease resistant peptide bonds to regulate their processing independent of tissue specific proteolysis and to stabilize these compounds in vivo, offering advantages over other forms of vaccines based on attenuated or inactivated micro organisms. Nadine L. Dudek, Patrick Perlmutter, Marie-Isabel Aguilar, Nathan P. Croft and Anthony W. Purcell [8] discuss the potential of peptide-based vaccines for the treatment of chronic viral diseases and cancer and review recent developments in the field of epitope discovery and peptide-based vaccines. Neuropeptides and their G-protein-coupled receptors are widely distributed throughout the body and they commonly occur with, and are complementary to, classic neurotransmitters. The neuroendocrine system can both directly and indirectly influence the developmental and functional activity of the immune system. The latter is designed to recognize and respond to a wide variety of foreign pathogens and injuries but may sometimes generate lymphocytes with high affinity to ubiquitously expressed self-antigens, causing a variety of chronic syndromes termed autoimmune diseases. Elena Gonzalez-Rey, Virginia Delgado-Moroto, Luciana Souza Moreira and Mario Delgado [9] evaluate the challenges that must be overcome before achieving neuropeptide clinical application and offer their opinion on how a physiologically functional neuropeptide system contributes to general health. Levels of high density lipoprotein and of its major protein component, apolipoprotein (apo) A-I, are strongly inversely correlated to risk of atherosclerosis and other vascular diseases. Several properties of apo A-I appear to contribute to this protection, such as removal of cholesterol from peripheral tissues to the liver (reverse cholesterol transport), anti-inflammatory and anti-oxidative activities, and modulation of vascular function. Some synthetic peptides, much smaller in size than apolipoproteins, can mimic several of the functional properties of apo A-I. Godfrey S. Getz, Geoffrey D. Wool and Catherine A. Reardon [10] summarize the recent advances in the investigation of apolipoprotein functions by use of peptide mimetics that may lead to novel therapeutic agents in the prevention of atherosclerosis and other vascular diseases. Clinical development of orally active peptide drugs is hampered by their unfavourable physicochemical properties, which limit their permeation across biological barriers (as intestinal lumen, intestinal mucosa or blood-brain barrier), and their lack of stability against enzymatic degradation, leading to short in vivo half-lives (generally < 30 min) and low oral bioavailability. The peptidomimetic strategy consists of altering the physicochemical characteristics of peptides without changing their biological activity. Luca Gentilucci, Rossella De Marco and Lucia Cerisoli [11] provide an up-to-date overview of the main classes of possible peptide modifications by introducing peptide bond mimetics, unnatural amino acids, conformational constraints or non-peptide scaffolds intended to increase peptide stability and improve the pharmacokinetic profile of bioactive natural peptides. A plethora of human pathogens are now resistant to all clinically significant antibiotics, causing a crisis in the treatment and management of infectious diseases but also presenting a clear danger to future public health (for example in clinical environment, with nosocomial infections). Based on their existence in natural host defence systems and their different mode of action relative to commercial antibiotics, antimicrobial peptides represent a new hope in discovering novel antibiotics against multi-resistant bacteria. The ease of generating peptide libraries in different formats has allowed a rapid adaptation of high-throughput assays to the search for novel antimicrobial peptides. Sylvie E. Blondelle and Karl Lohner [12] summarize the various library formats that lead to de novo antimicrobial peptide sequences as well as the latest structural knowledge and optimization processes aimed at improving the peptide selectivity. Antimicrobial peptides, naturally present in all organisms where they play a vital role in their innate immunity, can be active against several bacteria, fungi, viruses, protozoa and cancerous cells. Peptaibols are a family of peptides characterized by short chain lengths (20 residues), C-terminal alcohol residues and high levels of non-standard amino acids. They cause cell death either by disrupting the microbial cell membrane (their amphipathic, helical structure facilitates lytic pore formation in membranes) or by inhibiting extracellular polymer synthesis or intracellular functions. Herve Duclohier [13] explains how understanding the role of primary structure of antimicrobial peptides in their specificity and activity is essential for their rational design as drugs. Venomous species have evolved cocktails of bioactive peptides to facilitate prey capture. Given their often exquisite potency and target selectivity, venom peptides provide unique biochemical tools for probing the function of membrane proteins at the molecular level. Lys49- phospholipase A2 homologues constitute a large family of toxins present in the venoms of viperid snake species, which despite lacking catalytic activity, cause significant skeletal muscle necrosis, but also display antibacterial, antiendotoxic, antifungal, antiparasite, and antitumor activities. Bruno Lomonte, Yamileth Angulo and Edgardo Moreno [14] present an updated summary on the biomimetic actions exerted by such peptides, and highlight their potential value as molecular tools or as drug leads in diverse biomedical areas. I wish to thank all the authors and co-authors for their commitments and the anonymous reviewers who contributed by their constructive remarks to the excellence of this issue.