Peptidomimetics Protocols

Many physiologically important receptors and enzymes are regulated by their endogenous ligands and inhibitors. Nature chose to utilize these p- tides as chemical switches since they can be efficiently synthesized and - graded in cells, thus providing an immediate response to a fast changing environment. Such properties, so critical in cell survival, make peptides less than ideal drug candidates. Other frequently desired properties in drug m- ecules include oral bioavailability, the ability to cross membranes, including the blood-brain barrier, and sufficient stability for administration 1-2 times a day. In spite of these obstacles, some natural peptides and proteins are ind- putably successful medicines and have become drugs of choice. Further - vances in peptide-based pharmaceuticals are critically dependent on both new delivery methods and new chemical approaches to the conversion of these molecules to druglike entities. In addition, peptides are also the natural sta- ing points for optimization of their pharamacological and chemical prop- ties, which may lead to superior drugs. Peptidomimetics Protocols deals with both aspects of peptide pharmaceuticals, through the tools of modern s- thetic and medicinal chemistry. The last decade has witnessed a steady stream of new synthetic approaches to peptide mimetics, compounds that replace phy- ologically vulnerable peptide functionalities with chemical modules of - creased stability and cellular penetration. The chapters have been written by both academic and industrial chemists, and focus on the practical synthetic preparation of peptide mimetics.

A peptidomimetic is a small protein-like chain designed to mimic a peptide with adjusted molecular properties such as enhanced stability or biological activity. It is a very powerful approach for the generation of small-molecule-based drugs as enzyme inhibitors or receptor ligands. Peptidomimetics in Organic and Medicinal Chemistry outlines the concepts and synthetic strategies underlying the building of bioactive compounds of a peptidomimetic nature. Topics covered include the chemistry of unnatural amino acids, peptide- and scaffold-based peptidomimetics, amino acid-side chain isosteres, backbone isosteres, dipeptide isosteres, beta-turn peptidomimetics, proline-mimetics as turn inducers, cyclic scaffolds, amino acid surrogates, and scaffolds for combinatorial chemistry of peptidomimetics. Case studies in the hit-to-lead process, such as the development of integrin ligands and thrombin inhibitors, illustrate the successful application of peptidomimetics in drug discovery.

The last two decades have seen significant advances in peptide drug discovery, with peptide and modified peptides (peptidomimetics) providing the basis for active pharmaceutical ingredients applied across disease specialties; since 2000, 28 new, noninsulin peptide drugs have been approved worldwide, with several achieving market success. However, many researchers and clinicians still lack basic knowledge of peptide and peptidomimetic therapeutics and their potential to treat disease. Peptide and Peptidomimetic Therapeutics: From Bench to Beside offers applied, evidence-based instruction in developing and applying peptide therapeutics in disease treatment, driving drug discovery, and improving patientcare. Here, researchers, clinicians, and students will find tools to harness the full power of peptides and peptidomimetics, improving the bioavailability, stability, efficiency, and selectivity of new therapeutics and their application in treatment plans. More than 20 leaders in the field share their approaches for identifying and advancing peptide and peptidomimetic therapeutics. Topics examined run from "bench to bedside", beginning with fundamental peptide science, protein-protein interactions, and peptide synthesis. Later chapters examine modes for peptide drug delivery, including cell penetration peptide and peptidomimetic delivery, as well as targeting of specific disease types; peptide therapeutics as applied to infectious disease, cancer, metabolic disorders, neurodegenerative disorders, and skin disorders, in addition to antiparasitic and immunosuppressive peptidomimetics, are discussed in-depth.

The worldwide impact of infection with human immunodeficiency virus type 1 (HIV- is reflected in the cumulative number ofHIV- 1 infections, which is now predicted to exceed 40 million by the year 2000---equivalent to the n- ber of humans who perished in World War II. The medical and scientific - sponse to the HIV-1 pandemic has steadily grown since its recognition in 1981. The outlay by the United States alone for HIV research funded by the National Institutes of Health in 1997 was $1. 4 billion. Laboratory-based HIV research has brought together academic clinicians, retrovirologists, molecular biologists, and immunologists in the formation of research teams attempting to dissect the viral and host factors contributing to disease pathogenesis. Increasing focus is being placed on those aspects of viral biology and host immune responses that bear on the development of vaccines to prevent HIV infection. HIVProtocols reflects the state of HIV research in several ways. First, chapters are organized into four sections: Virology, Molecular Biology, Humoral Immunology, and Cellular Immunology. This organization is a natural consequence of the diverse scientific disciplines that have been attracted to HIV research. Second, the chapters reflect such diverse research directions as viral coreceptor usage, quantitation of viral genomes, HIV promoter function, B-cell epitope mapping, and measurements of T-cell function, each of which bears on the goal of understanding the viral and host immune responses that will be critical to the design of effective preventive vaccines.

This latest addition to the Methods in Molecular Medicine series, Anti- ral Methods and Protocols, is opportune because there is an increasing int- est in discovering compounds that are effective against both chronic and acute viral infections. A number of the methods described in the volume are unp- lished and their inclusion indicates the speed at which this field is moving. This volume is not a review but each chapter contains methods validated by the experts who have spent time in developing the protocols. The hallmark of this series is the comprehensive way in which the me- ods are described, which includes a list of all the reagents needed for each protocol. Of importance is the section on tips and pitfalls that the authors have discovered while developing their protocols. The manual itself is designed to be used by researchers in universities and industry who are familiar with a range of biological techniques but who want to set up quickly a novel assay system. We encourage a dialog between readers and authors, which may also result in useful collaborations.

A collection of cutting-edge techniques for detecting most of the major viruses that afflict mankind, including influenza, hepatitis, herpes, polio, mumps, HIV, and many more. The techniques are well-tested, easily reproducible, and readily employ all the new technologies-PCR, RIA, ELISA, and latex-agglutination-that have revolutionized the field. These methods not only make it possible to do the necessary analysis in hours instead of days, but can also be automated in a laboratory havng only low levels of biological containment. Frequently, the protocols for viruses causing human diseases can be adapted to similar viruses of veterinary importance. Through its state-of-the-art methods a physician can, for the first time, determine early in a viral infection which antiviral drug should be used and minimize the period of treatment to avoid unnecessary side effects.

Laboratory studies in hemostasis have traditionally focused on abn- malities of platelet function or the quantitative and qualitative disorders that affect the proteins involved in blood coagulation. However, over the last 10 years there has been an explosion in our understanding of the molecular bases that underlie many of the inherited and acquired disorders of hemostasis. Many of these disorders are now routinely diagnosed and assessed by methods that involve genotypic analysis. Indeed in the late 1990s the distinction between molecular methods for research and for routine diagnosis is becoming incre- ingly blurred. The techniques and approaches that are used in hemostasis are manifold and published in isolation in a variety of publications. The aim, therefore, of this volume Hemostasis and Thrombosis Protocols is to pull together, into a single volume, the variety of techniques that are frequently used in the field of hemostasis. We have targeted this volume at laboratories who wish to move into the field of molecular hemostasis or who may already have some expe- ence in this area but wish to develop new areas of research and diagnosis. The chapters are wide-ranging and hopefully provide a broad overview of the d- fering applications in which these standard techniques can be used. Though the articles may appear relatively specific, the techniques contained within them are applicable to the study of many different disorders and we hope that they provide a series of ideas and concepts well-suited to problem solving.