Proteases as Targets for Therapy

Proteolytic enzymes and their natural antagonists, the protease inhibitor pro teins, play a crucial role in the physiology and pathology of living organisms including humans. Remark able advantages revealed their wide functional context. Proteases digest food proteinase in the digestive tract and liberate poly peptide hormones, stimulating gastric and pancreatic secretion. Proteases are involved during fertilization in sperm - egg interaction, ovulation, ovum implantation and parturition. Proteases of the renin-angiotensin and kallikrein-kinin systems act synergistically to generate blood pressure regu lating polypeptides. In wound healing a battery of proteases is involved in the proteolytic cascades of clotting, fibrinolysis and tissue repair.Another battery of very different proteases directs the immune defense via several routes, i.e. complement activation, antigen presentation, the generation of chemokines and chemotaxins directing phagocytes to the site of injury or infection and the generation of cell-stimulating factors such as cytokines regulating the inflam matory response of the organism.Granzymes contribute to the toxicity of lym phocytes or killer cells,caspases regulate physiological cell death and calpains intracellular signaling cascades.The energy-dependent proteasome-ubiquitin system controls highly efficientl y the activity or level of intracellular proteins, including cell-cycle regulators, transcription and signal transduction factors, oncoproteins and short-lived metabolic enzymes.And this listing is far from complete.

Klappentext

This volume is the first to combine latest information on viral, microbial and cellular proteolytic enzymes as potential targets for human therapeutics. Proteases control a large array of physiological reactions, and are involved in a variety of pathological processes for which effective medications are currently needed and/or being sought after. Although protease inhibitors have been investigated for many years, few have been employed therapeutically. Recent break- through by HIV protease inhibitors as therapeutic drugs has re-encouraged the search for inhibitors of other proteolytic enzymes. Klaus von der Helm, who described the first viral protease has brought leading experts together to discuss not only the success and problems of clinical use and continuing prospects, but to review further potential drug targets. This volume provides detailed information and evaluations of key viral, bacterial, fungal, and cellular proteases as potential future drug candidates.

Inhalt
Section I. Human Immunodeficiency Virus Protease Inhibitors.- 1 The Road to Fortovase. A History of Saquinavir, the First Human Immunodeficiency Virus Protease Inhibitor.- 2 Clinical Experience with Human Immunodeficiency Virus Protease Inhibitors: Antiretroviral Results, Questions and Future Strategies.- 3 The Nature of Resistance to Human Immunodeficiency Virus Type-1 Protease Inhibitors.- 4 The Next Generation of Human Immunodeficiency Virus Protease Inhibitors: Targeting Viral Resistance.- Section II. Other Viral (Non-HIV) Protease Inhibitors.- 5 The Proteinases Encoded by Hepatitis C Virus as Therapeutic Targets.- 6 The Human Herpes-Virus Proteases.- 7 The 3C Proteinases of Picornaviruses and Other Positive-Sense, Single-Stranded RNA Viruses.- 8 Adenovirus Proteinase-Antiviral Target for Triple-Combination Therapy on a Single Enzyme: Potential Inhibitor-Binding Sites.- 9 Proteinases as Virulence Factors in Bacterial Diseases and as Potential Targets for Therapeutic Intervention with Proteinase Inhibitors.- 10 Parasite Proteases as Targets for Therapy.- Section III. (Non-Viral) Proteases Involved in Diseases.- 11 Host Proteinases as Targets for Therapeutic Intervention.- 12 The Role of Metalloprotease Inhibitors in Cancer and Chronic Inflammatory Diseases.- 13 The Tumor Necrosis Factor-? Converting Enzyme.- 14 Serine Elastases in Inflammatory and Vascular Diseases.- 15 Inhibitors of Thrombin and Factor Xa.- 16 Inhibitors of Papain-Like Cysteine Peptidases in Cancer.- 17 Caspases and Their Natural Inhibitors as Therapeutic Targets for Regulating Apoptosis.- 18 Proteasome and Apoptosis.- 19 Proteolytic Processing of the Amyloid Precursor Protein of Alzheimer's Disease.- 20 Presenilins and ?-Amyloid Precursor Protein-Proteolytically Processed Proteins Involved inthe Generation of Alzheimer's Amyloid ? Peptide.