Current Medicinal Chemistry - Volume 12, Issue 13, 2005

This volume is a selection of up today review articles on the thematic area: “Bioactive Peptides for Immune Disease Therapy”. In particular, book contains nine articles selected from several hot topics on Drug Design presented at the International Medicinal Chemistry Conference entitled: “Medicinal Chemistry: Drug Discovery and Design” held in Patras, March 11-13, 2004. Research and review papers describe current status and perspectives for immune system-mediated diseases in which important peptides such as Myelin Basic Epitope Peptides, Sequential Oligopeptide Carriers, Mucines, Corticotropin-Release Hormone Neuropeptides, HIV Peptides, Cytokines, play a key role in the regulation of immune system and provide important information for drug design and therapy. Articles are written by leading scientists in this field who have put in an intense effort to provide the current perspective and a comprehensive overview of the state of knowledge about methods and strategies in the immunotherapy of diseases such as Multiple Sclerosis, AIDS and other autoimmune diseases. Peptide research on drug discovery and design is an important field in the development of novel constrained peptide analogues or “peptide mimetics”, with the potential to generate important new drugs for disease therapy . Peptides control numerous body processes, and, as such, represent an untapped wellspring of new drugs for treating a variety of diseases. Knowledge of peptide action is important in rational drug design. Articles intend to assist the reader to get a global understanding of the recent research activities in the field of Drug Discovery and Design for immune disease therapy. I would like to thank and express my deepest appreciation to all contributors in this book. In particular, to the authors for generously contributing their time and expertise in the preparation of this issue. I appreciate the invitation by Current Medicinal Chemistry in providing the suitable and high-standard forum through which important findings of this research will become available to the scientific community as well as the assistance of Dr. Spyros Deraos for editing this issue In this regard I greatly appreciate the honor given to me by the Editor-In-Chief in entrusting me as a Guest Editor of this special issue. Finally, I am thankful and amply rewarded for extending my knowledge on the immune peptides field during the process of reading and editing the articles.

Nowadays, the use of synthetic carriers as biochemical reagents and immunogens is entering a new phase. The multimeric nature of these constructs, the unambiguous composition and the ease, reliability and versatility of their production, make this type of carriers well-suited to various biotechnological and biochemical applications for diagnostic purposes, protein mimetics, antiviral agents, vaccines, drug and gene delivery vehicles. This review aims to briefly summarize the different types of synthetic carriers currently in use and will be focused on an innovative type of multifunctional helicoid carrier-foldamer, named SOCn-I, II, which was successfully developed in our laboratory. Our concept was to construct an artificial template with structural rigidity and regularity, so as the peptide epitopes/pharmacophore groups could be anchored without any conformational restriction and steric hindrance as demonstrated by conformational studies using 1H-NMR, CD and FT-IR. SOCn-I,II were used as antigenic substrates in developing immunoassays of high sensitivity, specificity and reproducibility, as well as potent immunogens to generate site-specific antibodies. To this end, we emphasize on the application of SOCn carriers covalently bearing a 'built-in' adjuvant, for the preparation of totally synthetic peptide-based vaccines for human use.

The presentation of peptides derived from tumor associated proteins (TAAs) by the major histocompatibility complex (MHC) to T cell receptor (TcR) initiates a cascade of events that constitute the immune response. Eliciting an effective immune response, however, requires the coordinated regulation of both the cellular and humoral arms of the immune system. The design of effective peptide-based vaccines for cancer immunotherapeutic applications, therefore, requires intimate knowledge and understanding of peptide-MHC (pMHC) as well as TcR-pMHC interactions. Despite the wealth of information available to date from X-ray crystallographic and biological studies, the task of rationally designing peptide-based vaccines that can effectively prevent and/or treat cancer cell proliferation remains challenging. The complexity of interactions involved are not readily predictable and are further complicated by the involvement of surrounding molecules in vivo, which can lead to reduced biological activity and/or unwanted side effects. Furthermore, the delivery of peptide-based vaccines into the cell, for further processing and presentation to effector cell, represents an additional challenge which needs to be addressed. The incorporation of appropriate chemical entities into peptide-based vaccines can improve cellular uptake thereby enhancing biological activity. Finally, the susceptibility of peptide-based vaccines to enzymatic degradation warrants the need for the incorporation of non-natural amino acids, retro-inversion and/or cyclization to improve bioavailability essentially reducing the required dosage with minimum side effects.

Basement membranes are specialized extracellular matrices that surround certain cell types (muscle cells, adipose cells, etc) and are present under the basal surface of cells exhibiting polarity (epithelial, endothelial and mesothelial cells). They have a unique macromolecular composition, consisting mainly of type IV collagen isoforms, laminin isoforms, entactin/nidogen, and perlecan. These components self associate and interact with each other to form networks. Other macromolecules may be found in specialized basement membranes. In this short review, the role of selected basement membrane proteins in autoimmune diseases will be highlighted. As an example, Goodpasture's syndrome will be presented and the relatively long quest for identification of the antigenic epitope on specific domains of the α3(IV)NC1 will be summarized. Chagas disease will be discussed as an example of laminin-mediated autoimmunity, with emphasis on the role of sugarbased antigenic epitope(s) will be presented. Immune-mediated tubulointerstitial nephritis will be introduced and the role of a synthetic peptide in detecting proximal tubule damage in acute renal failure will be discussed. Auto-immune diseases where other basement membrane macromolecules are involved will be mentioned. Finally, the importance of understanding the functions served by domains at close proximity to the antigenic epitope(s) will be highlighted.

Hypothalamic CRF plays a central role in the coordination of endocrine and behavioral responses to stress and it is also involved in the pathophysiology of several neuropsychiatric diseases including depression, anxiety and addiction. In the mammals, the CRF family of peptides includes CRF, urocortin (Ucn), Ucn I, and Ucn II while was enriched with new members, the urocortins. Their biological effects are mediated by the CRF1 and CRF2 receptors, which belong to the G-protein-coupled receptor super family. Multiple research groups have demonstrated during the last decade the expression of the CRF peptides and their receptors in several components of the immune system and their participation in the ad hoc regulation of inflammatory phenomena. Non-peptide CRF1 antagonists have been recently synthesized for the treatment of CNS related diseases, such as anxiety, depression and drug abuse. In the gastrointestinal tract, these compounds open new therapeutic options in the treatment of lower-GI inflammatory diseases associated to CRF, such as the chronic inflammatory bowel syndromes, irritable bowel disease and ulcerative colitis while Ucn, Ucn I, Ucn II or synthetic non-peptide CRF2 agonists may be useful in the treatment of upper-GI inflammatory diseases. In human endometrium, CRF1 antagonists may be used as abortive agents interfering with the inflammatory phenomena taking place during the implantation of the conceptus. They thus may represent a new class of nonsteroidal inhibitors of implantation. These two examples illustrate the potential therapeutic significance of the CRH in regulating inflammatory phenomena in an ad hoc approach without affecting the rest of the immune system.

Experimental allergic encephalomyelitis (EAE) is a T helper 1 (Th1) mediated autoimmune disease and the principal animal model for multiple sclerosis (MS). Like MS, EAE is characterized by a coordinated inflammatory attack on the myelin sheath in the central nervous system (CNS), with damage to axons. No matter whether the ideal animal model is not yet available, much knowledge concerning the pathogenesis of MS has been achieved through studies on EAE. Dissecting the underlying immune mechanisms provided recognition of several myelin antigens that are vulnerable in autoimmune attack. The beneficial effect and the mechanism of action of a number of the currently used immunomodulating agents in MS therapy were first indicated in EAE. Altered peptide ligands (APL) can modulate T-cell responses to native peptide antigens implicated in the pathogenesis of autoimmune diseases such as MS and EAE. However, peptide therapy is hindered due to the sensitivity of peptides to proteolytic enzymes as well as due to some immune-mediated side effects. A number of cyclic myelin peptide analogs seem to be potential candidates in maintaining the biological function of the original peptide and effective in controlling inflammation in EAE. Additional data regarding the immunomodulating and neuroprotective effect of these much promising agents is required. Based on the data from studies on EAE models, clinical trials should also be designed in order to elucidate the impact of such APL-induced immune responses in MS disease activity. These clinical trials should carefully incorporate monitoring of both clinical, neuroimaging and immunological parameters.

Confronting Multiple Sclerosis requires as an underlying step the manipulation of immune response through modification of Myelin Basic Protein peptides. The aim is to design peptidic or nonpeptidic molecules that compete for recognition of self-antigens at the level of antigen presentation. The rational approach is to substitute residues that serve as anchors for the T-Cell Receptor with others that show no binding at all, and those that serve as Major Histocompatibility Complex II anchors with others that present increased binding affinity. The resulting structure, hence, retains normal or increased MHC II binding properties, but fails to activate disease-inducing T-cells. This rational design can only be achieved by identifying the structural requirements for binding of the natural peptide to MHC II, and the anchor residues with their corresponding specific pockets in the binding groove. The peptide-MHC II complex then interacts with the TCR; thus, an additional way to trigger the desired immune response is to alter secondary anchor residues as well as primary ones. In this review, the structural requirements for binding of MBP peptides to MHC II are presented, as are the mechanism and key features for TCR recognition of the peptide-MHC II complex.

Autoimmune diseases are many, have an overall prevalence of about 3% of the world population, affecting more women than men, and their incidence is influenced by genetics and the environment. It is currently thought that the immune response of a genetically predisposed individual to an environmental pathogen, under the influence of inadequate or non-functional immunoregulatory mechanisms, can lead to the development of an autoimmune disease. Advances in the treatment of autoimmune diseases follow a better understanding of the abnormalities in the cellular activity pathways and the resulting, often permanent, imbalance of the pro- and anti-inflammatory cytokine expression profiles. Over the past few years, there has been a dramatic change in the therapeutic regimens employed in autoimmune diseases, with soluble receptors, monoclonal antibodies and molecular mimetics enhancing or gradually replacing conventional immunosuppressive therapies. New biologicals have been developed, targeting defined pathways of the adaptive immune response. One approach towards the therapeutic management of autoimmune diseases involves the design and use of peptide analogs of disease-associated epitopes to be used as immunomodulatory drugs. Peptides can target cell-functions directly, by interfering with the formation of the tri-molecular complex MHCPeptide- TCR, and/or they can target soluble mediators such as cytokines or their receptors, eventually replacing monoclonal antibody therapies. This review offers an update on the treatment modalities of certain prototypic autoimmune diseases, based on the current knowledge of disease pathogenesis, with emphasis on cell activation and cytokine expression profiles.

Infection of target host cells by the human immunodeficiency virus-1 (HIV-1) is a multi-step process involving a series of conformational changes in the viral gp120 and gp41 proteins. Gp120 binding to the main cell receptor, CD4, on the surface of cells expressing this molecule, and interaction with the cell chemokine receptors CCR5 and CXCR4, are among the key events for HIV-1 infection. These steps are crucial for the virus and offer potential therapeutic targets. For this reason, understanding the structure and the physicochemical characteristics of the gp120 in relation to these interactions has drawn much attention. This review article focuses on the biologically important V3 region of the gp120 and summarizes the functional role, the sequence variation and the conformational features of V3 peptides, which are important for co-receptor selectivity, specificity and interaction. Synthetic V3 peptides have been extensively studied by NMR spectroscopy and Xray crystallography, in solution or in solid state, in their free or bound form, and valuable information was generated with the aim to be exploited in the design of new, effective inhibitors of HIV-1 infection. The features of the potential gp120 interacting sites on the two chemokine co-receptors, CCR5 and CXCR4, are also discussed, and co-receptor blocking molecules under clinical trial are also reported.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and loss of neurological function, local macrophage infiltrate and neuroantigenspecific CD4+T cells. MS arises from complex interactions between genetic, immunological, infective and biochemical mechanisms. Although the circumstances of MS etiology remain hypothetical, one persistent theme involves immune system recognition of myelin-specific antigens derived from myelin basic protein, the most abundant extrinsic myelin membrane protein, and/or another equally suitable myelin protein or lipid. Knowledge of the biochemical and physico-chemical properties of myelin proteins and lipids, particularly their composition, organization, structure and accessibility with respect to the compacted myelin multilayers, becomes central to understanding how and why myelin-specific antigens become selected during the development of MS. This review focuses on the current understanding of the molecular basis of MS with emphasis: (i) on the physical-chemical properties, organization, morphology, and accessibility of the proteins and lipids within the myelin multilayers; (ii) on the structure-function relationships and characterization of the myelin proteins relevant to the manifestation and evolution of MS; (iii) on conformational relationships between myelin epitopes which might become selected during the development of MS; (iv) on the structure of MHC/HLA in complex with MBP peptides as well as with TCR, which is crucial to the understanding of the pathogenesis of MS with the ultimate goal of designed antigen-specific treatments.