With contributions by numerous experts

In this ground-breaking practical reference, the family of aspartic acid proteases is described from a drug developer's perspective. The first part provides a general introduction to the family of aspartic acid proteases, their physiological functions, molecular structure and inhibition. Parts two to five present various case studies of successful protease inhibitor drug design and development, as well as current and potential uses of such inhibitors in pharmaceutical medicine, covering the major therapeutic targets HIV-1 protease, renin, beta-secretase, gamma-secretase,plasmepsins and fungal proteases. A ready reference aimed primarily at professionals in the pharmaceutical industry, as well as for anyone studying proteases and their function.

Proteolysis is an irreversible posttranslational modification affecting each and every protein from its biosynthesis to its degradation. Limited proteolysis regulates targeting and activity throughout the lifetime of proteins. Balancing proteolysis is therefore crucial for physiological homeostasis. Control mechanisms include proteolytic maturation of zymogens resulting in active proteases and the shut down of proteolysis by counteracting endogenous protease inhibitors. Beyond the protein level, proteolytic enzymes are involved in key decisions during development that determine life and death – from single cells to adult individuals. In particular, we are becoming aware of the subtle role that proteases play in signaling events within proteolysis networks, in which the enzymes act synergistically and form alliances in a web-like fashion. Proteases come in different flavors. At least five families of mechanistically distinct enzymes and even more inhibitor families are known to date, many family members are still to be studied in detail. We have learned a lot about the diversity of the about 600 proteases in the human genome and begin to understand their physiological roles in the degradome. However, there are still many open questions regarding their actions in pathophysiology. It is in this area where the development of small molecule inhibitors as therapeutic agents is extremely promising. Approaching proteolysis as the most important, irreversible post-translational protein modification essentially requires an integrated effort of complementary research disciplines. In fact, proteolytic enzymes seem as diverse as the scientists working with these intriguing proteins. This book reflects the efforts of many in this exciting field of research where team and network formations are essential to move ahead.

Cancer-Leading Proteases: Structures, Functions, and Inhibition presents a detailed discussion on the role of proteases as drug targets and how they have been utilized to develop anticancer drugs. Proteases possess outstanding diversity in their functions. Because of their unique properties, proteases are a major focus of attention for the pharmaceutical industry as potential drug targets or as diagnostic and prognostic biomarkers. This book covers the structure and functions of proteases and the chemical and biological rationale of drug design relating to how these proteases can be exploited to find useful chemotherapeutics to fight cancers. In addition, the book encompasses the experimental and theoretical aspects of anticancer drug design based on proteases. It is a useful resource for pharmaceutical scientists, medicinal chemists, biochemists, microbiologists, and cancer researchers working on proteases.

Proteases are enzymes that essentially "eat" protein. Without proteases, infectious organisms cannot properly mount an attack against a host. It is for this reason that proteases have become popular targets for drug discovery. Research has shown that if you can inhibit the protease, you can defend against the invading microbe. The defense against HIV, the virus that causes AIDS, is the best-documented case of the efficacy of protease inhibitors. Researchers are now trying to deploy this strategy against several infectious agents. This book gives information that is useful in that search.Proteases of Infectious Agents collects reviews from leading experts describing the latest information on the properties of key enzymes from a variety of viruses, fungi, and parasites. Each chapter provides the critical facts needed to initiate a drug discovery effort in that particular area. Includes information on the basic biology and function of proteases Provides global survey of current research efforts in protease inhibitors Illustrates how structure-based drug design targets effective and selective compounds Highlights important diseases that provide economically important targets Describes the role of proteases as important new targets for drug discovery

This book provides a comprehensive overview of the proteases involved in programmed cell death. It presents a focused yet extensive discussion on proteolytic enzymes such as caspases, HtrAs, granzymes, calpains and cathepsins as well as laboratory protocols related to enzymology and apoptosis. Mouse model systems and non-invasive imaging techniques in apoptosis-related diseases such as cancer and neurodegeneration are also covered in this book. While slowly unravelling the complexities of apoptosis in chapter one, the next three chapters individually elaborate on different classes of proteases that play key roles in the initiation, progression and execution of programmed cell death. The last two chapters complete this discussion by describing different laboratory methodologies and therapeutic advances involving apoptotic proteases. Protocols portraying in vitro and ex vivo colorimetric and fluorescence-based enzyme kinetic studies as well as cell death assays are explained in the fifth chapter. Preclinical in vivo models and non-invasive imaging in apoptosis to understand the complexities of disease progression and their contribution toward therapeutics is recounted in the last chapter. The book spans topics related to both fundamental and applied biology. It would therefore be equally appealing and informative to scientists working in the field of apoptosis and those who are investigating mechanisms of proteases and enzymes in general. The protocols would certainly benefit both graduate and undergraduate students working in the related fields and provide useful leads for drug design to translational biologists involved in neurodegeneration and cancer research.

This book provides a comprehensive overview of the multifaceted field of protease in the cellular environment and focuses on the recently elucidated functions of complex proteolytic systems in physiology and pathophysiology. Given the breadth and depth of information covered in the respective contributions, the book will be immensely useful for researchers working to identify targets for drug development. Multidisciplinary in scope, the book bridges the gap between fundamental and translational research, with applications in the biomedical and pharmaceutical industry, making it a thought-provoking read for basic and applied scientists engaged in biomedical research. Proteases represent one of the largest and most diverse families of enzymes known, and we now know that they are involved in every aspect of a given organism’s life functions. Under physiological conditions, proteases are regulated by their endogenous inhibitors. However, when the activity of proteases is not correctly regulated, disease processes such as tumour progression, vascular remodelling, atherosclerotic plaque progression, ulcer, rheumatoid arthritis, Alzheimer’s disease and inflammation can result. Many infective microorganisms require proteases for replication or use them as virulence factors, which has facilitated the development of protease-targeted therapies for a variety of parasitic diseases.

During the past decade, the rapid growth of molecular and cellular knowledge of macrophages, as a specialized host defense and homeostatic system, has begun to offer attractive targets for therapeutic intervention. Macrophages play a central role in a wide range of disease processes, from genetically determined lysosomal storage diseases, to acute sepsis, chronic inflammation and repair, tissue injury and cell death. Under- or overactivity of macrophage clearance, immune effector functions and responses to metabolic abnormalities contribute to common disorders such as autoimmunity, atherosclerosis, Alzheimer’s disease and major infections including AIDS and Tuberculosis. Whilst the goals of therapeutic intervention based on improved understanding of macrophage functions and their contribution to pathogenesis may seem self evident, there are considerable difficulties in producing useful new agents. The present volume covers a range of subjects and provides opportunities for a more focused macrophage-targeted approach. The individual chapters review selected topics briefly, to place cellular processes and molecular targets in perspective. Overall, the volume should provide a broad sample of the state of the art. Useful reviews and references in the literature are cited within individual chapters.

Serine proteases play significant roles in healh and human disease. Abnormal expression and activities of serine proteases have been linked to the pathogenesis of many diseases. The book presents correlation between serine proteases and human diseases. It helps the reader understand classification, catalytic mechanism and types of serine proteases and their role in human disease pathogenesis at mechanistic level. The chapters explain the role of serine proteases in various diseases including respiratory disorders and cancer. It also covers the therapeutic importance of serine proteases as drug target and explains the mechanistic insights of serine proteases inhibitors. Serine protease are known to play crucial role in biological processes but disturbance in their equilibrium can result in serious health conditions. To maintain homeostasis, serine protease inhibitors come in action and inhibit proteases. Several serine protease inhibitors have been identified and many more are being designed as novel compounds for inhibitions of proteases that provide management of comorbidities. Therefore, this book will serve as a useful reference for students and researchers to understand physiological role of serine proteases and their association with initiation and progression of human diseases. It will also help to develop some strategies to develop serine proteases inhibitors as drug target of serine proteases at cellular and molecular level.