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Viral Proteases And Their Inhibitors

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Viral Proteases and Their Inhibitors

Viral Proteases and Their Inhibitors Book
Author : Satya Prakash Gupta
Publisher : Academic Press
Release : 2017-07-03
ISBN : 0128096829
Language : En, Es, Fr & De

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Book Description :

Viral Proteases and Their Inhibitors provides a thorough examination of viral proteases from their molecular components, to therapeutic applications. As information on three dimensional structures and biological functions of these viral proteases become known, unexpected protein folds and unique mechanisms of proteolysis are realized. This book investigates how this facilitates the design and development of potent antiviral agents used against life-threatening viruses. Users will find descriptions of each virus that detail the structure and function of viral proteases, discuss the design and development of inhibitors, and analyze the structure-activity relationships of inhibitors. This book is ideal biochemists, virologists and those working on antiviral agents. Provides comprehensive, state-of-the-art coverage of virus infections, the virus lifecycle, and mechanisms of protease inhibition Analyzes structure-activity relationships of inhibitors of each viral protease Presents an in-depth view of the structure and function of viral proteases

Viral Proteases and Antiviral Protease Inhibitor Therapy

Viral Proteases and Antiviral Protease Inhibitor Therapy Book
Author : Uwe Lendeckel,Nigel M. Hooper
Publisher : Springer Science & Business Media
Release : 2009-06-19
ISBN : 9048123488
Language : En, Es, Fr & De

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Book Description :

The 8th volume in the Proteases in Biology and Disease series focuses on the role of proteases in virus function and their potential as anti-viral targets. Viral infections are still difficult to threat and some remained life-threatening diseases in spite of antiviral drug research over decades. Proteases are still regarded as an Achilles’ heel of the pathogens and, thus, protease inhibitors may help to handle the known and the emerging viral threads. The book discusses viral proteases of the most important pathogenic viruses, responsible for severe diseases: AIDS, SARS, Hepatitis, Cytomegalovirus, T-cell lymphotropic virus, Picornavirus. This book focuses specifically on the viral proteases, crucial prerequisites for viral entry into cells and viral replication. Viral proteases represent an important pharmaceutical target. The current stage of protease inhibitor development and therapy are summarised and discussed by experts in the field. This volume represents a timely and valuable continuation of the Proteases in Biology and Disease series. The reader will learn the potential for proteases as targets for effective anti-virals. This book will be a valuable source of information on viral proteases and provoke further research in this important field.

Viral Proteases and Antiviral Protease Inhibitor Therapy

Viral Proteases and Antiviral Protease Inhibitor Therapy Book
Author : Uwe Lendeckel,Nigel M. Hooper
Publisher : Springer
Release : 2009-08-29
ISBN : 9789048123759
Language : En, Es, Fr & De

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Book Description :

The 8th volume in the Proteases in Biology and Disease series focuses on the role of proteases in virus function and their potential as anti-viral targets. Viral infections are still difficult to threat and some remained life-threatening diseases in spite of antiviral drug research over decades. Proteases are still regarded as an Achilles’ heel of the pathogens and, thus, protease inhibitors may help to handle the known and the emerging viral threads. The book discusses viral proteases of the most important pathogenic viruses, responsible for severe diseases: AIDS, SARS, Hepatitis, Cytomegalovirus, T-cell lymphotropic virus, Picornavirus. This book focuses specifically on the viral proteases, crucial prerequisites for viral entry into cells and viral replication. Viral proteases represent an important pharmaceutical target. The current stage of protease inhibitor development and therapy are summarised and discussed by experts in the field. This volume represents a timely and valuable continuation of the Proteases in Biology and Disease series. The reader will learn the potential for proteases as targets for effective anti-virals. This book will be a valuable source of information on viral proteases and provoke further research in this important field.

Proteases of Infectious Agents

Proteases of Infectious Agents Book
Author : Ben Dunn
Publisher : Elsevier
Release : 1999-07-01
ISBN : 9780080525747
Language : En, Es, Fr & De

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Book Description :

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

Characterization of Viral Proteases from Norwalk Virus Poliovirus and Transmissible Gastroenteritis Virus Using a Fluorescence Resonance Energy Transfer Assay

Characterization of Viral Proteases from Norwalk Virus  Poliovirus  and Transmissible Gastroenteritis Virus Using a Fluorescence Resonance Energy Transfer Assay Book
Author : Venkata Kiran Pasupulleti
Publisher : Unknown
Release : 2012
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Positive sense RNA viruses include diverse groups of viruses that cause a wide variety of diseases in humans and animals. Most of these viruses encode proteases that cleave the viral polyprotein into intermediate or mature functional proteins during virus replication. As these proteases play a critical role in virus replication, they represent an attractive target for the development of antiviral drugs. In this study, the main goal was to establish assay systems and characterize the enzymatic activity of related proteases from Norwalk virus (NV), poliovirus, and transmissible gastroenteritis virus (TGEV). These proteases share several common characteristics including a typical chymotrypsin-like fold, a Cys residue as a nucleophile in the catalytic triad (or dyad) composed of Cys, His and Glu (or Asp) residues, and a preference for a Glu or Gln residue at the P1 position on the substrate. We cloned and expressed proteases from these viruses and characterized their enzymatic activities using a fluorescence resonance energy transfer (FRET) assay using a specific FRET substrate corresponding to each viral protease. First, assay conditions of the FRET assay was optimized for each virus protease. Second, inhibition profiles of each virus protein were investigated using five commercially available standard protease inhibitors (chymostatin, leupeptin, antipain, TPCK, and TLCK). The inhibition studies showed that TPCK inhibited NV, poliovirus, and TGEV proteases with varying strength, and chymostatin inhibited only NV protease. All other inhibitors had little effects on the virus proteases. The established FRET assays should facilitate screening potential antivirals.

Search for New Antiviral Compounds Using Fragment Screening Methodology

Search for New Antiviral Compounds Using Fragment Screening Methodology Book
Author : Anonim
Publisher : Unknown
Release : 2015
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Picornaviridae are among the most diverse and oldest known viral families that include many important pathogens of humans and animals. They are small, icosahedral (+)ssRNA viruses, causing a variety of diseases, such as encephalitis, and poliomyelitis. Vaccines are available for poliovirus, hepatitis A virus and foot-and mouth disease virus, but no effective prophylaxis is implemented for other picornaviruses. Thus far, anti-viral research has focused on the capsid, whereas inhibitors targeting non-structural proteins (i.e. proteases, helicases, polymerases) have remained largely unaddressed. The project was focused on structural and biochemical characterization of the enterovirus-B93 (EVB93) 3C protease alone and in complex with several covalent inhibitors. The second objective was to identify the first non-covalent potent inhibitors of the EV-B93 3C protease and their further biochemical, antiviral, and structural evaluation. This work studied the in-vitro proteolytic activity of the EV-B93 3C protease, alone and in the presence of two known covalent inhibitors - rupintrivir and compound 1, as well as three low molecular weight covalent inhibitors - NZO, NZN and DB5_60. The crystal structures of the EV-B93 3C protease alone and in complex with rupintrivir, compound 1, and NZN molecule were solved at high resolution (1.57, 1.50, 1.32, and 1.73 Å, respectively). The structures revealed that the protein adapts a chymotrypsinlike fold similarly to other picornavirus 3C proteases and possesses His-40, Glu-71 and Cys-147 as a catalytic triad. The STD NMR-based fragment screening was performed to select non-covalent binders of the EV-B93 3C protease. Validation and profiling of the most promising non-covalent hits were done using thermal shift assay (TSA), surface plasmon resonance (SPR), and proteolytic activity assay. 44 analogs of the most potent molecule were evaluated in the in-vitro proteolytic activity assay. The most active compound displayed IC50 value of 5 flM. Further chemical optimization was performed resulting in more efficient inhibitor with similar IC50 value. Selected analogs were tested in the in-vitro proteolytic assay against analogous 3C proteases from the following viruses: human rhinovirus-A49, enterovirusD68, aichivirus A, porcine sapelovirus, and equine rhinitis B virus. All compounds exhibited good inhibitory activity against three of the tested proteases. Furthermore, in a cell-based proteolytic assay and an antiviral assay the compounds did not exhibit either proteolytic or antiviral activity, which may be explained by several factors such as lack of cell permeability, low solubility and/or high toxicity. Extensive co-crystallization and soaking trials were performed to obtain crystal structures of noncovalent complexes of the EV-B93 3C protease with the most potent compounds. Regrettably, no additional electron density was identified in the proteolytic active site. Bioinformatics docking simulations suggested potential binding mode of the optimized compound. These pointed to the presumed pockets occupied by the compound that interact with the two conserved residues from the catalytic triad. Since the most potent compound is a relatively large and rigid molecule, it is unable to bind to the protease without its previous rearrangement, which is unfavorable in the crystalline state of the protein. This observation may explain the inability of the non-covalent molecules to co-crystallize with EV-B93 3C protease. The results obtained in this study may aid the design of potent, noncovalent antivirals targeting enteroviral 3C proteases.

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development Book
Author : Arun K. Ghosh,Bruno D. Chapsal
Publisher : Elsevier Inc. Chapters
Release : 2013-05-07
ISBN : 0128062037
Language : En, Es, Fr & De

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Book Description :

The development of HIV protease inhibitors (PIs) and their inclusion in highly active antiretroviral therapies (HAARTs) marked the beginning of a treatment breakthrough in the management of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). The HAART treatment regimen can cut HIV viral load to undetectable levels. Nonetheless, the rapid emergence of HIV drug resistance has continued to seriously compromise long-term treatment options for HIV-infected patients. Our structure-based design strategy to develop PIs that specifically target the enzyme's backbone atoms has resulted in a number of very potent inhibitors with superior drug resistance profiles. Of particular note, our development of stereochemically defined bis(tetrahydrofuranyl) urethane as a high-affinity P2 ligand has led to the development of exceedingly potent inhibitors. One of these inhibitors, darunavir, has shown exceptional potency against the HIV-1 virus and superior activity against multi-PI-resistant viral strains. Our backbone binding strategy was corroborated with detailed crystal structure analyses of darunavir-bound protease complexes which revealed a series of conserved interactions between the inhibitor and key backbone atoms of HIV-1 protease. Darunavir first received accelerated US Food and Drug Administration approval in 2006 for highly treatment-experienced patients with little therapeutic options. It has now become a leading PI in the fight against HIV infection and drug resistance.

Proteases and Their Inhibitors in Cancer Metastasis

Proteases and Their Inhibitors in Cancer Metastasis Book
Author : J-M. Foidart,R.J. Muschel
Publisher : Springer Science & Business Media
Release : 2002
ISBN : 1402009232
Language : En, Es, Fr & De

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Book Description :

In recent years, serine proteases and matrix metalloproteinases (MMPs) have gained considerable attention in tumor biology. For most of these proteases, their expression is a reliable indication of ongoing tissue remodeling. This book provides a comprehensive evaluation of the mechanisms of action of proteases and their inhibitors in tumor biology. The first part provides the reader with a selective overview of the molecular biology of serine proteases, MMPs and their physiological inhibitors. The most important proteases and their physiological as well as synthetic inhibitors are evaluated in the most relevant models of experimental and human cancer. The clinical aspects are also taken into account. This volume offers an update on this challenging aspect of cancer treatment, its interest bias, and possible clinical implication.

Activation of Viruses by Host Proteases

Activation of Viruses by Host Proteases Book
Author : Eva Böttcher-Friebertshäuser,Wolfgang Garten,Hans Dieter Klenk
Publisher : Springer
Release : 2018-05-22
ISBN : 3319754742
Language : En, Es, Fr & De

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Book Description :

This book will give an overview on viruses undergoing proteolytic activation through host proteases. The chapters will be organized in three themed parts, the first part describing respective viruses and their characteristics in detail. In the second part the molecular and cellular biology of the proteases involved as well as their physiological functions will be further explored. The third part will contain a chapter on protease inhibitors that are promising tools for antiviral therapy. This book will engage scholars in virology and medical microbiology as well as researchers with an interest in enzymology and protein structure and function relationship.

Viral Replication Enzymes and their Inhibitors Part A

Viral Replication Enzymes and their Inhibitors Part A Book
Author : Anonim
Publisher : Academic Press
Release : 2021-10-23
ISBN : 0128234695
Language : En, Es, Fr & De

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Book Description :

Viral Replication Enzymes and their Inhibitors Part A, Volume 49, the latest release in the Enzymes series, highlights new advances in the field, with this new volume presenting interesting chapters on a variety of related topics. Provides the authority and expertise of leading contributors from an international board of authors Presents the latest release in The Enzymes series

Innovations in Proteases and Their Inhibitors

Innovations in Proteases and Their Inhibitors Book
Author : Francesc X. Avilés
Publisher : Unknown
Release : 1993
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Download Innovations in Proteases and Their Inhibitors book written by Francesc X. Avilés, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.

Structure guided Design Synthesis and Evaluation of Macrocyclic and Peptidomimetic Inhibitors of Viral Proteases

Structure guided Design  Synthesis and Evaluation of Macrocyclic and Peptidomimetic Inhibitors of Viral Proteases Book
Author : Vishnu C. Damalanka
Publisher : Unknown
Release : 2017
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Human noroviruses are the primary cause of non-bacterial acute gastroenteritis worldwide and are associated with high morbidity and a heavy economic burden. In the U.S. alone noroviruses account for ~21 million cases, resulting in 70,000 hospitalizations and 800 deaths annually, and impact most severely the young and elderly, and immunocompromised individuals. Combating norovirus infections presents a challenge because of their high infectivity, ease of transmission, the dearth of norovirus-specific therapeutics/prophylactics and vaccines, and a poor understanding of norovirus pathophysiology. Noroviruses are icosahedral, single-stranded, positive sense RNA viruses whose genome (7-8 kb) is comprised of three open reading frames (ORFs) that encode a 200 kDa polyprotein (ORF1), a major capsid protein VP1 (ORF2) and a small basic protein VP2 (ORF3). Following translation of the viral genome, the viral polyprotein is cleaved by the viral-encoded 3C-like protease (NS6pro) to generate structural and nonstructural proteins. NS6pro is essential for virus replication, consequently, it is an attractive target for the discovery of anti-norovirus small molecule therapeutics. Norovirus 3CL protease (NS6pro) is a cysteine protease with a Cys-His-Glu catalytic triad, an extended binding site, and a chymotrypsin-like fold. The protease displays a near absolute requirement for a P1 glutamine residue or equivalent. The enzyme is an attractive target for the discovery and development of anti-norovirus therapeutics and prophylactics. The dissertation describes for the first time the structure-guided design of cell-permeable macrocyclic inhibitors of the protease, as well as pertinent structural, biochemical, and cell-based studies.

Proteases and Their Receptors in Inflammation

Proteases and Their Receptors in Inflammation Book
Author : Nathalie Vergnolle,Michel Chignard
Publisher : Springer Science & Business Media
Release : 2011-08-03
ISBN : 9783034801577
Language : En, Es, Fr & De

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Book Description :

Proteases are everywhere from prokaryotes to eukaryotes, from virus to bacteria and in all human tissues, playing a role in many biological functions. Among these functions, the inflammatory reaction is of particular interest. In inflamed tissues, proteases can have a microbial and/or host origin and are involved not only in tissue remodeling, but also in specific signaling to resident or inflammatory cells, thereby contributing to the innate immune response. This volume presents all advances in our knowledge of the role proteases and their inhibitors play in various diseases associated with inflammatory response. Mechanisms involved in protease signaling to cells are presented, and the different types of proteases that are present at inflammatory sites and their effects on the course of inflammation are discussed. Finally, the evidence for considering proteases and their receptors as potential molecular targets for therapeutic interventions in the treatment of inflammatory diseases is discussed in the context of specific organ inflammatory pathologies (the lung, gastrointestinal tract, skin, joints, etc.).

Cancer Causing Viruses and Their Inhibitors

Cancer Causing Viruses and Their Inhibitors Book
Author : Satya Prakash Gupta
Publisher : CRC Press
Release : 2014-05-16
ISBN : 1466589779
Language : En, Es, Fr & De

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Book Description :

Cancer-causing viruses, also called oncoviruses, play a key role in the development of certain cancers. They contribute to genetic changes that disrupt the cell cycle machinery, interfering with functions such as cell growth. Cancer-Causing Viruses and Their Inhibitors presents a plethora of research from internationally reputed contributors who discuss different types of oncoviruses, their mechanisms of invasion and growth, and their life cycles. The book begins with an overview of the oncoviruses discovered to date and includes a brief description of their structures, genotypes, replication, and mechanisms of infection leading to cancers. It then explores several of these viruses in detail, including: Human T-cell leukemia virus type 1 (HTLV-1) Hepatitis C virus (HCV) Epstein–Barr virus (EBV) Human papilloma virus (HPV) Human herpes virus 8 (HHV-8)/Kaposi’s sarcoma-associated herpes virus (KSHV) Human immunodeficiency virus (HIV/AIDS) Oncolytic viruses This book is an essential reference for those working in virology, oncology, and biotechnology. The discoveries presented will enable researchers and clinicians to optimize both historical and current approaches to anti-viral therapies.

Applications of Metal Organic Frameworks and Their Derived Materials

Applications of Metal Organic Frameworks and Their Derived Materials Book
Author : Inamuddin,Rajender Boddula,Mohd Imran Ahamed,Abdullah M. Asiri
Publisher : John Wiley & Sons
Release : 2020-05-04
ISBN : 111965095X
Language : En, Es, Fr & De

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Book Description :

Metal–organic frameworks (MOFs) are porous crystalline polymers constructed by metal sites and organic building blocks. Since the discovery of MOFs in the 1990s, they have received tremendous research attention for various applications due to their high surface area, controllable morphology, tunable chemical properties, and multifunctionalities, including MOFs as precursors and self-sacrificing templates for synthesizing metal oxides, heteroatom-doped carbons, metal-atoms encapsulated carbons, and others. Thus, awareness and knowledge about MOFs and their derived nanomaterials with conceptual understanding are essential for the advanced material community. This breakthrough new volume aims to explore down-to-earth applications in fields such as biomedical, environmental, energy, and electronics. This book provides an overview of the structural and fundamental properties, synthesis strategies, and versatile applications of MOFs and their derived nanomaterials. It gives an updated and comprehensive account of the research in the field of MOFs and their derived nanomaterials. Whether as a reference for industry professionals and nanotechnologists or for use in the classroom for graduate and postgraduate students, faculty members, and research and development specialists working in the area of inorganic chemistry, materials science, and chemical engineering, this is a must-have for any library.

Development of a Cell based Assay for the Discovery of Novel Protease Inhibitors for Dengue Virus

Development of a Cell based Assay for the Discovery of Novel Protease Inhibitors for Dengue Virus Book
Author : Anonim
Publisher : Unknown
Release : 2013
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Most viruses rely on the processing of their proteome by viral and/or host proteases (PRs). This is the case of Dengue Virus (DenV), a member of the Flaviviridae family and the most common and widespread arthropod-borne viral infection of humans. DenV currently has no effective vaccines or antiviral drug treatments. Developing antiviral drugs that target DenV NS2B cofactor/NS3 protease could potentially be one of the most successful strategies in combating DenV pathogenesis and spread. The primary goal of this project is to develop an assay that will provide a robust, cell-based, high throughput method to quickly identify novel PR inhibitors for DenV. Hilton and Wolkowicz developed a cell-based assay to monitor the catalytic activity of HIV-1 PR in T-cells. This project will adapt the assay from HIV-1 PR to the NS2B/NS3 protease complex of the four serotypes of DenV and monitor the proteolytic activity via a similar GFP reporter system. In addition, all of the necessary components of the reporter system and the DenV adapted Gal4/NS2B/NS3 fusion will be stably expressed in a genetically bar coded non-adherent T-cell line and an adherent hepatocyte cell line. The final version of the assay will be a cell-based, high throughput, multiplexed system designed to efficiently screen hundreds of thousands of candidate inhibitors of DenV NS3 protease activity. In addition, the assay can be utilized to further illuminate the cellular localization of various NS2B transmembrane deletion mutants, how these mutants effect NS3 protease activity ex vivo, and possibly discover novel cleavage targets of NS2B/NS3.

Proteases as Targets for Therapy

Proteases as Targets for Therapy Book
Author : Klaus, von der Helm,Bruce D. Korant,John C. Cheronis
Publisher : Springer Science & Business Media
Release : 2012-12-06
ISBN : 3642570925
Language : En, Es, Fr & De

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Book Description :

With contributions by numerous experts

Retroviral Proteases

Retroviral Proteases Book
Author : Lawrence C. Kuo,Jules A. Shafer
Publisher : Gulf Professional Publishing
Release : 1994-10-06
ISBN : 9780121821425
Language : En, Es, Fr & De

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Book Description :

Methods included in this volume apply to the expression and characterization of retroviral proteases and their inhibitor/substrate design.

Studies on Hepatitis Viruses

Studies on Hepatitis Viruses Book
Author : Satya Prakash Gupta
Publisher : Academic Press
Release : 2018-06-20
ISBN : 0128133317
Language : En, Es, Fr & De

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Book Description :

Studies on Hepatitis Viruses: Life Cycle, Structure, Functions, and Inhibition presents the latest on this systemic infection that predominantly affects the liver with inflammation that can be acute or chronic. Hepatitis viruses have been the subject of intense study in the last twenty years, with a wealth of information related to their lifecycle, structure, functions and inhibition being presented. This book compiles the most important developments and research, giving users a very useful guide on this evolving area of virology and medicinal chemistry. Provides comprehensive, state-of-the-art coverage of hepatitis virus infections, the virus' lifecycle, and mechanisms of protease inhibition Analyzes structure-activity relationships of inhibitors of viral hepatitis Presents an in-depth view of the structure and function of viral hepatitis Discusses classification, epidemiology, pathogenesis, natural history, clinical manifestations, diagnosis, complications, associated disorders and animal models