Current Pharmaceutical Design - Volume 16, Issue 28, 2010

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.

Cells of multicellular organisms need to communicate and have evolved different mechanisms of intercellular communication, the most direct and quickest of which is through channels that directly link the cytoplasms of adjacent cells. In metazoans, intercellular channels result from the docking of two hemichannels, hexameric torus of junctional proteins (connexins being the most known) around an aqueous pore. Junctional channels and hemichannels are not passive conduits as they had been regarded for a long time but their permeability is finely tuned by complex mechanisms that have just begun to be identified, the delay being partly due to limited availability of specific pharmacological tools. Peptides have a number of advantages over other molecules in terms of specificity and affinity for targets. Some of them interact with membrane receptors, activating a signaling transduction cascade leading to modifications in the expression of gap junctional proteins or the functional state of channels. A second approach is based on the use of so-called mimetic peptides (also known as gap peptides) that mimic a short sequence of gap junction proteins and have been shown to attenuate processes downstream of the putative channel activity. They also represent very useful tools to investigate the structure of domains of gap junction proteins. This review presents an overview of the literature on peptides targeting gap junctional structures.

G protein-coupled receptors (GPCRs) are considered to represent the most promising drug targets; it has been repeatedly said that a large fraction of the currently marketed drugs elicit their actions by binding to GPCRs (with cited numbers varying from 30-50%). Closer scrutiny, however, shows that only a modest fraction of (∼60) GPCRs are, in fact, exploited as drug targets, only ∼20 of which are peptide-binding receptors. The vast majority of receptors in the humane genome have not yet been explored as sites of action for drugs. Given the drugability of this receptor class, it appears that opportunities for drug discovery abound. In addition, GPCRs provide for binding sites other than the ligand binding sites (referred to as the “orthosteric site”). These additional sites include (i) binding sites for ligands (referred to as “allosteric ligands”) that modulate the affinity and efficacy of orthosteric ligands, (ii) the interaction surface that recruits G proteins and arrestins, (iii) the interaction sites of additional proteins (GIPs, GPCR interacting proteins that regulate G protein signaling or give rise to G protein-independent signals). These sites can also be targeted by peptides. Combinatorial and natural peptide libraries are therefore likely to play a major role in identifying new GPCR ligands at each of these sites. In particular the diverse natural peptide libraries such as the venom peptides from marine cone-snails and plant cyclotides have been established as a rich source of drug leads. High-throughput screening and combinatorial chemistry approaches allow for progressing from these starting points to potential drug candidates. This will be illustrated by focusing on the ligand-based drug design of oxytocin (OT) and vasopressin (AVP) receptor ligands using natural peptide leads as starting points.

Orexin A and B (also named hypocretin 1 and 2) are 33 and 28 amino acid-containing neuropeptides, respectively, derived from prepro-orexin (prepro-hypocretin) which is localized in the lateral and perifonical areas of the hypothalamus. Two G-protein coupled receptor subtypes, OX1 and OX2, were identified. Orexin-containing fibers and OX receptors are widely distributed in the central nervous system. Orexins have been implicated in the arousal, rewarding, energy homeostasis, autonomic central control and antinociceptive systems. Subtype-selective peptide agonists and antagonists and non-peptide antagonists, but not non-peptide agonists, have been developed. This review summarizes the studies investigating the antinociceptive effects of orexins in various animal models of pain, including trigeminovascular pain, and their cellular mechanisms. Orexins are antinociceptive at both spinal and supraspinal levels. The antinociceptive effect of orexin A is comparable to opioids but orexin B is less or not effective. This effect is opioid-independent and mainly mediated through OX1 receptors. Some animal studies suggest that endogenous orexins may be released during postoperative and inflammatory, but not acute, pain states, or during some stress conditions, which may contribute to stress-induced analgesia. Purinergic P2X and glycine receptors are proposed to be involved in orexin-induced spinal antinociception. The supraspinal sites of actions might involve the posterior hypothalamus, which contributes to the trigeminovascular nociception, and the ventrolateral periaqueductal gray, which mediates descending pain inhibition. Endocannobinoids and nociceptin/orphanin FQ were found to interplay with orexins in nocicpetive processing. Further studies are required to elucidate the receptor subtype-specific mechanism(s) and clinical implications of orexin-induced antinociception.

This review discusses the development of the active site-directed protein tyrosine phosphatase (PTP) inhibitors based on peptides and some closely related nonpeptidic scaffolds. A straightforward approach is to substitute various nonhydrolyzable analogs for the phosphotyrosine (pTyr) of optimal or physiological phosphopeptide substrates of PTPs. The advances in small molecule peptidic PTP inhibitors and their nonpeptidic derivatives have been greatly aided by X-ray crystallographic and NMR spectrometric studies. Given the importance of PTPs in disease-associated signal transduction and the continuing progress in PTP drug discovery, some clinically useful PTP inhibitors may emerge in the near future.

Peptide nucleic acids (PNA) are artificial structural mimics of nucleic acids capable of sequence specific hybridization to both RNA and DNA. Thus they have obvious potential as gene targeting agents for drug discovery approaches. An overview with emphasis on recent progress on RNA “interference” (antisense), targeting of duplex DNA and gene targeted repair and transcription interference using PNA, as well as on PNA delivery and potential PNA anti-infectives is given.

Overproduction of reactive oxygen species (ROS) under pathophysiologic conditions is part of the disease process. These ROS are released from different sources, and in particular from mitochondria. Although the molecular mechanisms responsible for mitochondria- mediated disease processes are unclear, oxidative stress seems to play an important role. ROS are essential to cell function, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects that excessive ROS production can produce. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions. The antioxidants available until now have not proved to be particularly effective against many of these disorders. It is possible that these antioxidants do not reach the sites of free radical generation, especially when mitochondria are the primary source of ROS. Recent developments in mitochondria-targeted antioxidants have moved closer to providing protection against mitochondrial oxidative damage. The SS (Szeto-Schiller) peptide antioxidants represent a novel approach that employs the targeted delivery of antioxidants to the inner mitochondrial membrane. These SS peptides scavenge hydrogen peroxide and peroxynitrite and inhibit lipid peroxidation. By reducing mitochondrial ROS, they inhibit mitochondrial permeability transition and cytochrome c release, thus preventing oxidant-induced cell death. Preclinical studies support the use of these peptides for ischemia-reperfusion injury and neurodegenerative disorders. Although peptides have often been considered to be poor drug candidates, the few that have been studied are promising agents for the treatment of diseases.

The mitochondrion provides the stage for the interplay of molecular interactions that regulate apoptosis via the intrinsic pathway. The release of apoptogenic factors from this compartment constitutes a critical juncture in this apoptotic pathway. Regulation of the integrity of the outer mitochondrial membrane (OMM) is the task of the Bcl-2 family of proteins. A network of interactions between the various subgroups of the family decides the apoptotic fate of a cell and, as such, an imbalance within this network can lead to a variety of disease states. In particular, over-expression of pro-survival Bcl-2 family proteins is a hallmark of many cancers. Here we discuss recent advances in targeting the Bcl-2 family with both peptides and small molecules.

With recent advances in the design and delivery of peptide-based therapeutics there has been a growing interest in the use of peptides in vaccine design. Moreover, functional dissection and proteomic analysis of the immunogenic epitopes of proteins from pathogenic micro-organisms, cancers and self-tissues targeted by autoimmune responses, have broadened the range of target epitopes and given clues to enhancing peptide immunogenicity. Consistent with these observations; 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. We 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.

Because there are no particular molecular signatures of self, autoimmunity is the inevitable evolutionary price of being able to make effective responses against a wide variety of pathogens by the immune system. Without the various phenomena referred to as immune tolerance, the organism would surely self-destruct. Considerable evidence suggests that various endogenous neuropeptides play a major role in the education of our immune system to be self-tolerant. The fact that neuropeptides regulate various layers involved in maintenance of tolerance, including regulation of the balance between pro-inflammatory and anti-inflammatory responses and between self-reactive Th1/Th17 cells and regulatory T cells, makes them attractive candidates for the development of new therapies for the treatment of autoimmune disorders. Here we use the vasoactive intestinal peptide of a prototype of immunomodulatory neuropeptide to review the most relevant data found for other neuropeptides with similar characteristics, including melanocyte-stimulating hormone, urocortin, adrenomedullin, neuropeptide Y, cortistatin and ghrelin. We also evaluate the challenges that must be overcome before achieving their clinical application and offer our opinion on how a physiologically functional neuropeptide system contributes to general health.

Elevations of HDL levels or modifying the inflammatory properties of HDL are being evaluated as possible treatment of atherosclerosis, the underlying mechanism responsible for most cardiovascular diseases. A promising approach is the use of small HDL apoprotein- related mimetic peptides. A number of peptides mimicking the repeating amphipathic -helical structure in apoA-I, the major apoprotein in HDL, have been examined in vitro and in animal models. Several peptides have been shown to reduce early atherosclerotic lesions, but not more mature lesions unless coadminstered with statins. These peptides also influence the vascular biology of the vessel wall and protect against other acute and chronic inflammatory diseases. The biologically active peptides are capable of reducing the proinflammatory properties of LDL and HDL, likely due to their high affinity for oxidized lipids. They are also capable of influencing other processes, including ABCA1 mediated activation of JAK2 in macrophages, which may contribute to their anti-atherogenic function. The initial studies involved monomeric 18 amino acid peptides, but tandem peptides are being investigated for their anti-atherogenic and antiinflammatory properties as they more closely resemble the repeating structure of apoA-I. Peptides based on other HDL associated proteins such as apoE, apoJ and SAA have also been studied. Their mechanism of action appears to be distinct from the apoA-I based mimetics.

Functions and properties of native peptides vary from highly specific antibiotics or cytotoxic antitumor drugs, to hormones, neurotransmitters, immunomodulators, etc. Despite their potential utility as therapeutic agents, there are problems connected with the use of natural peptides, due to the low stability against proteolysis, resulting in a short duration of in vivo activity, and in a low bioavailability. One way to overcome these disadvantages is the use of modified peptides, the so called peptidomimetics. Overall, the less peptide character in a drug candidate, the more stable it is towards protease cleavage. A huge number of non-peptidic scaffolds have been reported in the literature; nevertheless, several cases have failed to reproduce the activity of the precursor peptide when the scaffold itself contains relevant pharmacophore elements. Therefore, quasi-peptides still maintain their appeal for applications in medicinal chemistry. For the large number of different unnatural amino acids and peptidomimetics, the overview cannot be all-inclusive. This review focuses on modified peptides in which the peptide character is still preponderant, with particular emphasis on the chemical methodologies utilized to introduce the modifications.

While a well-established process for lead compound discovery in for-profit companies, high-throughput screening is becoming more popular in basic and applied research settings in academia. The development of combinatorial libraries combined with easy and less expensive access to new technologies has greatly contributed to the implementation of high-throughput screening in academic laboratories. While such techniques were earlier applied to simple assays involving single targets or based on binding affinity, they have now been extended to more complex systems such as whole cell-based assays. In particular, the urgent need for new antimicrobial compounds that would overcome the rapid rise of drug-resistant microorganisms, where multiple target assays or cell-based assays are often required, has forced scientists to focus onto high-throughput technologies. Based on their existence in natural host defense 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. Similarly, the availability nowadays of high-quantity and high-quality antimicrobial peptide data has permitted the development of predictive algorithms to facilitate the optimization process. This review summarizes 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 peptides selectivity.

In this review, the antimicrobial properties of a number of peptides are described. We first deal with helical linear peptides such as the well-known gramicidin, magainins, melittin, and other less well-known or more recently discovered peptides. Then, betasheet peptides (defensins isolated from insects and also from mammalian tissues) and cyclic peptides like amphotericin B are described before the properties of peptaibols (containing the non-coded amino acid Aib) are discussed. Alamethicin remains the prototype of this class and its biophysical properties (mostly focussing on channel- or pore-formation in planar lipid bilayers) were and are still intensively studied. On the whole, we show how biophysical studies can explain the antimicrobial action of this ever expanding family of peptides.

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. The main structural determinants of this toxic effect have been experimentally mapped to a region near their C-terminus (115-129), which combines cationic and hydrophobic/aromatic amino acid residues. Short (13-mer) synthetic peptides representing this C-terminal region can mimick several of the effects of Lys49 PLA2 homologues. In addition to their ability to damage muscle cells, these peptides display antibacterial, antiendotoxic, antifungal, antiparasite, and antitumor activities, as well as VEGF-receptor 2 (KDR)-binding and heparin-binding properties. Modifications of their sequences have shown possibilities to enhance their effects upon prokaryotic cells, while decreasing toxicity for eukaryotic cells. This review presents an updated summary on the biomimetic actions exerted by such peptides, and highlights their potential value as molecular tools or as drug leads in diverse biomedical areas.