Current Protein and Peptide Science, Vol. 6, No. 3, 2005

Olivier Loreal, Christelle Haziza-Pigeon, Marie-Berengere Troadec, Lenaick Detivaud, Bruno Turlin, Brice Courselaud, Guennadi Ilyin and Pierre Brisso

[Abstract]

Abstracts

[Back to top] Editorial

Knut Adermann

During the past two years, three new peptide drug approvals by the US Food and Drug Administration have attracted considerable attention: brain natriuretic peptide (BNP; Natrecor^®) for acute heart failure, parathyroid hormone fragment 1-34 (PTH; Teriparatide^®) for osteoporosis, and T-20 (enfuvirtide/Fuzeon^®) for HIV/AIDS. While BNP and PTH are human hormones or rather hormone fragments, T-20 corresponds to a functional domain of the HIV envelope protein gp41. It is remarkable that these drugs are used in different fields, such as cardiovascular (BNP), bone metabolism (PTH), and viral infection (T-20), demonstrating that a general reluctance towards peptide drugs widely observed a decade ago has now been largely overcome. Today, hundreds of peptides are in development and dozens are in clinical trials for a variety of diseases. Approvals of new peptide drugs for diabetes and obesity, for example, are expected soon. A part of this recent success is due to the significant progress that has been achieved in formulation, galenics and stabilization of these pharmapeptides. These accomplishments have helped to resolve some specific difficulties in developing peptides as therapeutic agents, in particular insufficient in vivo exposure, which is now no longer an insurmountable hurdle. Another difficult task in dealing with peptides was successfully tackled during the development of T-20: the production of multi 100 kg quantities, which was almost inconceivable at the time of the scientific discovery of this new peptide drug.

The pipeline for corresponding future accomplishments is being fueled in a large part through the discovery of novel naturally occurring peptides. These novel peptides can be developed into drugs themselves, and can also serve as leads for further refinement as necessary to optimize pharmaceutical properties. An overwhelming plethora of natural peptides from all living species is known today, and a rapid increase in novel structures and also new biological activities is anticipated. In parallel, methods, technologies and concepts such as phage display, rational drug design and the analysis of the quantitative structure-activity relationship (QSAR) allow design and development of modified peptides based on the natural structure, and a de novo assembly of peptides with defined structural and functional characteristics.

Against this background, this issue of Current Protein and Peptide Science highlights several areas in peptide research that are representative of the significant advances made recently. In the first, Hartley and Offord discuss a systematic approach to develop new peptide anti-HIV therapeutic agents from RANTES, a natural peptide ligand of chemokine receptors. Since the discovery that HIV infection requires specific binding to certain chemokine receptors, these cell surface proteins have become valid targets for the inhibition of viral infection. This review not only covers HIV/AIDS as a globally important clinical field, it also demonstrates how understanding and modelling of a receptor-ligand interaction can significantly contribute to the design and development of potential peptide drugs. In the second review, Armishaw and Alewood illustrate the use of invertebrate peptides to develop as research tools and drugs for human diseases. Tropical seas harbour many organisms that have developed effective chemical means for attack and defence. Particularly fascinating chemical weapons are the conotoxins, components of the venom of Co-nus snails. The numerous and diverse peptides of this class are ligands of ion channels, and they thus represent important neuropharmacological tools. Mägert and colleagues have outlined the role and potential of serine proteases and their endogenous inhibitors for skin biology. Proteases are proving to be very important and attractive therapeutic targets. Overexpression and an insufficient control of their enzymatic activity account for many disorders. The human body contains a large number of peptides that display antimicrobial activity. Beisswenger and Bals review the most important endogenous peptides of this type regarding their role in innate and adaptive immunity. An important aspect is that these peptides, originally thought to directly kill microbes, are indeed multi-functional substances. They thus represent opportunities for clinical research, but are also a scientific challenge. New natural peptides with diverse biological functions are steadily being discovered in a variety of organisms. Reverse pharmacology is a systematic approach to discover new ligands of G protein-coupled receptors based on genomic data of orphan receptors, i.e. receptors for which no endogenous ligand is known. Kutzleb and colleagues explain the power of this strategy using very recent examples of newly discovered peptides. A further report by Loréal and co-workers deals with hepcidin, a new peptide hormone with a unique structure involved in iron metabolism. Discovered independently by biochemical and genomic approaches, it completes our knowledge of iron-related disorders and might contribute to new diagnostics and therapeutics in this field.

The peptides and peptide classes discussed in this issue of Current Protein and Peptide Science are representative of many other examples. As analytical tools, in particular mass spectrometry, are being further developed regarding sensitivity, accuracy and throughput, it is anticipated that structures of a large number of novel peptides will soon be disclosed. Besides the fundamental importance of the biology of the peptides reviewed in the present articles, it is emphasized that the technologies used for their discovery and investigation represent an enormous range of research tools which will support future progress in different fields of peptide biology.

[Back to top] Engineering Chemokines to Develop Optimized HIV Inhibitors

Oliver Hartley and Robin E. Offord

Since the discovery that to enter target cells HIV uses receptors for the class of proteins known as chemokines, attempts have been made to generate anti-HIV molecules based on the chemokine ligands. A significant level of knowledge of the structure-activity relationships of chemokines has been amassed since the beginning of the 1990s. This, together with work that has elucidated the mechanisms underlying the inhibitory activity of chemokines, has guided not only the rational design of anti-HIV chemokine analogues, but also strategies by which chemokine variants with potent anti-HIV activity can be isolated from large libraries by phage display. This review summarizes the current knowledge about the structure-activity relationships and receptor biology of chemokines that is relevant to the development of analogues with anti-HIV activity. We present specific examples of engineered chemokine analogues with potent anti-HIV activity and describe the challenges that will need to be faced if these molecules are to be further developed for clinical applications. Finally, we discuss how these challenges might be met through further engineering of the molecules.

[Back to top] Conotoxins as Research Tools and Drug Leads

Christopher J. Armishaw and Paul F. Alewood

The complex mixture of biologically active peptides that constitute the venom of Conus species provides a rich source of ion channel neurotoxins. These peptides, commonly known as conotoxins, exhibit a high degree of selectivity and potency for different ion channels and their subtypes making them invaluable tools for unravelling the secrets of the nervous system. Furthermore, several conotoxin molecules have profound applications in drug discovery, with some examples currently undergoing clinical trials. Despite their relatively easy access by chemical synthesis, rapid access to libraries of conotoxin analogues for use in structure-activity relationship studies still poses a significant limitation. This is exacerbated in conotoxins containing multiple disulfide bonds, which often require synthetic strategies utilising several steps.

This review will examine the structure and activity of some of the known classes of conotoxins and will highlight their potential as neuropharmacological tools and as drug leads. Some of the classical and more recent approaches to the chemical synthesis of conotoxins, particularly with respect to the controlled formation of disulfide bonds will be discussed in detail. Finally, some examples of structure-activity relationship studies will be discussed, as well as some novel approaches for designing conotoxin analogues.

[Back to top] Serine Proteinase Inhibitors in the Skin: Role in Homeostasis and Disease

Hans-Jurgen Magert, Katrin Drogemuller and Michael Raghunath

Serine proteinases fulfill and facilitate a broad spectrum of biological processes. They are held in check by different specific inhibitors. This delicate balance can be disturbed by genetic defects or exogenous influences and has been shown as the underlying or promoting cause for a large number of different diseases. For instance, proteinases are under investigation as drug targets for cancer, infections, neurodegenerative diseases, osteoporosis, inflammatory disorders and many more. Dermatological research has contributed greatly to the appreciation of the complex regulatory network between serine proteinases and serine proteinase inhibitors. In addition, proteolytically trimmed proteinase-activated receptors (PARs) trigger keratinocyte proliferation and differentiation as well as leukocyte attraction and activation. New insights have been gained particularly concerning the progression of inflammatory disorders of the skin. This review summarizes the role of serine proteinase inhibitors in physiology and pathophysiology of the skin.

[Back to top] Functions of Antimicrobial Peptides in Host Defense and Immunity

Christoph Beisswenger and Robert Bals

Antimicrobial peptides (AMPs) are effector molecules of the innate immune system. AMPs have a broad antimicrobial spectrum and lyse microbial cells by interaction with biomembranes. Besides their direct antimicrobial function, they have multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells influencing diverse processes such as cytokine release, cell proliferation, angiogenesis, wound healing, chemotaxis, immune induction, and protease-antiprotease balance. Furthermore, AMPs qualify as prototypes of innovative drugs that may be used as antibiotics, anti-lipopolysaccharide drugs, or modifiers of inflammation. This review summarizes the current knowledge about the basic and applied biology of antimicrobial peptides and discusses features of AMPs in host defense and inflammation.

[Back to top] Discovery of Novel Regulatory Peptides by Reverse Pharmacology: Spotlight on Chemerin and the RF-amide Peptides Metastin and QRFP

Christian Kutzle, Annette Busmann, Martin Wendland and Erik Maronde

Reverse pharmacology is a screening technology that matches G protein-coupled receptors (GPCRs) with unknown cognate ligands in cell-based screening assays by detection of agonist-induced signaling pathways. One decade spent pursuing orphan GPCR screening by this technique assigned over 30 ligand/receptor pairs and revealed previously known or novel undescribed ligands, mostly of a peptidic nature. In this review, we describe the discovery, characterization of the structural composition, biological function, physiological role and therapeutic potential of three recently identified peptidic ligands. These are metastin, QRFP in a context of five RF-amide genes described in humans and the chemoattractant, chemerin. Metastin was initially characterized as a metastasis inhibitor. Investigations using ligand/receptor pairing revealed that metastin was involved in a variety of physiological processes, including endocrine function during pregnancy and gonad development. The novel RF-amide QRFP is implicated in food intake and aldosterone release from the adrenal cortex in the rat. Chemerin, first described as TIG2, is upregulated in tazarotene-treated psoriatic skin. By GPCR screening, bioactive chemerin was isolated from ovarial carcinoma fluid as well as hemofiltrate. Characterization as a chemoattractant for immature dendritic cells and analysis of the expression profile of metastin and its receptor suggested a physiological role of chemerin as a mediator of the immune response, inflammatory processes and bone development.

[Back to top] Hepcidin in Iron Metabolism

Olivier Loreal, Christelle Haziza-Pigeon, Marie-Berengere Troadec, Lenaick Detivaud, Bruno Turlin, Brice Courselaud, Guennadi Ilyin and Pierre Brissot

Hepcidin, which has been recently identified both by biochemical and genomic approaches, is a 25 amino acid polypeptide synthesized mainly by hepatocytes and secreted into the plasma. Besides its potential activity in antimicrobial defense, hepcidin plays a major role in iron metabolism. It controls two key steps of iron bioavailability, likely through a hormonal action: digestive iron absorption by enterocytes and iron recycling by macrophages. In humans, this could explain that low levels of hepcidin found during juvenile haemochromatosis and HFE-1 genetic haemochromatosis are associated with an iron overload phenotype. Conversely, an increase of hepcidin expression is suspected to play a major role in the development of anemia of chronic inflammatory diseases. However, the regulatory mechanisms of hepcidin expression are multiple, including iron-related parameters, anemia, hypoxia, inflammation and hepatocyte function. Therefore, many physiological and pathological situations may modulate hepcidin expression and subsequently iron metabolism. A better knowledge of the biological effects of hepcidin and of its expression regulatory mechanisms will clarify the place of hepcidin in the diagnosis and treatment of iron-related diseases.