Hiv 1 Protease As A Target For Antiretroviral Therapy
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Hiv 1 Protease As A Target For Antiretroviral Therapy
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Author : Ian William Windsor
language : en
Publisher:
Release Date : 2019
Hiv 1 Protease As A Target For Antiretroviral Therapy written by Ian William Windsor and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2019 with categories.
Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV employs three enzymes in its lifecycle, including a protease that enables maturation of polyprotein precursors. Despite decades of progress studying the lifecycle of HIV and elaboration of therapeutics targeting nearly every aspect of the viral life cycle, a cure remains elusive. Breakthroughs in HIV research have occurred alongside foundational advances of molecular biology, biotechnology, and medicinal chemistry, highlighting the importance revisiting old questions with new approaches. The goal of this thesis is to advance our biochemical knowledge of HIV-I protease and develop novel therapeutics targeting this key viral enzyme. In Chapter 1, I introduce HIV and the role that HIV-1 protease plays in life cycle and current treatment strategies. In Chapter 2, I describe an assay that enables the determination of sub-picomolar inhibition constants for competitive inhibitors of HIV-1 protease. This advance was made possible by a peptide substrate selected by phage display. I report in Chapter 3 the enhanced hydrogen bonding in the recognition of this peptide by HIV-1 protease as revealed by X-ray crystallography. The mechanism of aspartic proteases, including HIV-1 protease, has been the subject of numerous enzymology studies spanning over half a century. In Chapter 4, I reveal unappreciated non-covalent interactions within substrates of aspartic proteases that assist in catalysis. In addition to biochemical studies, this thesis includes chapters that account the development of novel antivirals. In Chapter 5, I describe the rational drug design of a boronic acid analog of the clinical inhibitor darunavir with improved potency. A limitation of boronic acids is metabolic instability; in Chapter 6, I reveal an intramolecular protecting group that can confer oxidative stability to boronic acids. Finally, in Chapter 7, I describe an engineering approach to inactivate human RNase 1. The inactivation relies on installing a substrate for HIV- I protease, the cleavage of which unmasks cytotoxic activity. Together these chapters describe new ways forward and novel therapeutics targeting HIV-1 protease. My thesis also includes an Appendix, which describes the elaboration of boronic acid-based covalent pharmacological chaperones of human transthyretin.
Introduction To Biological And Small Molecule Drug Research And Development
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Author : Arun K. Ghosh
language : en
Publisher: Elsevier Inc. Chapters
Release Date : 2013-05-07
Introduction To Biological And Small Molecule Drug Research And Development written by Arun K. Ghosh and has been published by Elsevier Inc. Chapters this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013-05-07 with Science categories.
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.
Advances In Hiv Treatment
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Author : Gene D. Morse
language : en
Publisher: Bentham Science Publishers
Release Date : 2016-12-04
Advances In Hiv Treatment written by Gene D. Morse and has been published by Bentham Science Publishers this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016-12-04 with Medical categories.
Advances in HIV Treatment: HIV Enzyme Inhibitors and Antiretroviral Therapy presents comprehensive and updated information on drug therapies used to treat and manage HIV infection in human patients. The volume is organized in to chapters detailing respective classes of HIV Drugs including HIV entry inhibitors, reverse transcriptase inhibitors (RTIs), integrase strand inhibitors (INSTIs), and protease inhibitors (PIs). Each chapter compiles background information, pharmacology and clinical aspects such as side effects on the specific classes of drugs represented. Available data for ongoing research for new targets, including vaccines is also presented. Readers will also find a useful introduction to HIV virology and pathogenesis as well as a comparison of the availability and activity of these agents in different populations, opening a discussion on the influence of genetics and resources in curbing the HIV epidemic. Advances in HIV Treatment: HIV Enzyme Inhibitors and Antiretroviral Therapy is, therefore, a holistic resource for researchers, healthcare professionals and clinicians interested in understanding antiretroviral drugs and the management of HIV infection/AIDS. The volume is also of interest to undergraduate and graduate students undertaking specialized courses in pharmacology and HIV/AIDS management.
Hiv 1 Integrase
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Author : Nouri Neamati
language : en
Publisher: John Wiley & Sons
Release Date : 2011-08-10
Hiv 1 Integrase written by Nouri Neamati and has been published by John Wiley & Sons this book supported file pdf, txt, epub, kindle and other format this book has been release on 2011-08-10 with Science categories.
This book comprehensively covers the mechanisms of action and inhibitor design for HIV-1 integrase. It serves as a resource for scientists facing challenging drug design issues and researchers in antiviral drug discovery. Despite numerous review articles and isolated book chapters dealing with HIV-1 integrase, there has not been a single source for those working to devise anti-AIDS drugs against this promising target. But this book fills that gap and offers a valuable introduction to the field for the interdisciplinary scientists who will need to work together to design drugs that target HIV-1 integrase.
The Future Of Hiv 1 Therapeutics
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Author : Bruce E. Torbett
language : en
Publisher: Springer
Release Date : 2015-04-22
The Future Of Hiv 1 Therapeutics written by Bruce E. Torbett and has been published by Springer this book supported file pdf, txt, epub, kindle and other format this book has been release on 2015-04-22 with Medical categories.
This volume thoroughly covers HIV-1 antiretrovirals currently in clinical use, together with their advantages and limitations. HIV-1 inhibitor resistance is discussed in detail, and critical assessments as to what will be required of future antiretrovirals in order to halt viral replication, reduce viral resistance, and alter the state of viral latency are presented. Experts at the forefront of HIV-1 research provide overviews of approaches from the fields of virology, chemical biology and structural biology for obtaining small molecule inhibitors that target viral regulatory and structural components at multiple points in the viral lifecycle. The individual chapters will appeal to scientists and clinicians alike.
Structure Function Studies Of Hiv 1 Protease
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Author : Bradley James Keusch
language : en
Publisher:
Release Date : 2016
Structure Function Studies Of Hiv 1 Protease written by Bradley James Keusch and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016 with Biochemistry categories.
HIV-1 is the causative agent of the devastating human disease Acquired Immunodeficiency Syndome (AIDS). While much progress has been made over the past two decades, HIV-1 remains a major global health concern. HIV-1 protease is 99-amino acid homodimer aspartyl protease that is essential to the life cycle of HIV. This has rendered it an attractive and very successful drug target. However, due to the high error rate of the HIV -1 reverse transcriptase, drug resistance mutations in the protease can develop very rapidly in some patients, rendering current protease inhibitors (one of the main classes of drug in common antiretroviral therapy) less effective or completely ineffective. In this thesis, we investigate the structural impact of a number of HIV-1 protease drug resistance mutations. These include L33F, which is selected for on darunavir treatment (one of the most prescirbed protease inhibitors), I47V, and V54I (which we identify as compensatory mutations involved in the tethering of the protease flaps and proper formation of the active site). A fuller understanding of the structural impact of these resistance mutations will hopefully facilitate the development of protease inhibitors that can overcome this common drug resistance.
Handbook Of Antimicrobial Resistance
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Author : Matthias Gotte
language : en
Publisher: Springer
Release Date : 2018-02-12
Handbook Of Antimicrobial Resistance written by Matthias Gotte and has been published by Springer this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018-02-12 with Medical categories.
While many volumes have been written about various aspects of antimicrobial resistance, this book is a comprehensive reference work. All manifestations of resistance are addressed: viral; bacterial, parasitical and fungal are given dedicated sections. The underlining molecular mechanisms, which depend not only on the microbe but on the specific drug (target), are highly diverse. This work discusses and compares the biological, biochemical and structural aspects of resistance and its evolution.
Design Of Anti Aids Drugs
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Author : Erik De Clercq
language : en
Publisher: Elsevier Publishing Company
Release Date : 1990
Design Of Anti Aids Drugs written by Erik De Clercq and has been published by Elsevier Publishing Company this book supported file pdf, txt, epub, kindle and other format this book has been release on 1990 with Medical categories.
There are several steps in the replicative cycle of human immunodeficiency virus (HIV) that could be considered as adequate targets for chemotherapeutic intervention, e.g., virus attachment to the cells, virus penetration and uncoating, transcription of the viral (RNA) genome to proviral DNA, integration of the proviral DNA into host cell DNA, transcription of the proviral precursor proteins to mature viral proteins, assembly and release ('budding') of the viral particles. These processes depend on, and are regulated by, specific viral proteins. This makes many of these processes and proteins plausible targets for the design of selective inhibitors. The contributions assembled in this book are aimed at presenting what is known anno 1990 about (1) the different steps in the HIV replicative cycle that could be considered as targets for anti-HIV agents, (2) the compounds that interact with these targets and offer promise as candidate drugs for the treatment of HIV infection, and (3) to the extent that it has been resolved, the mechanism of interaction of the anti-HIV agents with their putative targets.
Nano Inspired Biosensors For Protein Assay With Clinical Applications
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Author : Genxi Li
language : en
Publisher: Elsevier
Release Date : 2018-08-29
Nano Inspired Biosensors For Protein Assay With Clinical Applications written by Genxi Li and has been published by Elsevier this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018-08-29 with Science categories.
Nano-inspired Biosensors for Protein Assay with Clinical Applications introduces the latest developments in nano-inspired biosensing, helping readers understand both the fundamentals and frontiers in this rapidly advancing field. In recent decades, there has been increased interest in nano-inspired biosensors for clinical application. Proteins, e.g. antigen-antibody, tumor markers and enzymes are the most important target in disease diagnosis, and a variety of biosensing techniques and strategies have been developed for protein assay. This book brings together all the current literature on the most recent advances of protein analysis and new methodologies in designing new kinds of biosensors for clinical diagnostic use. Provides a single source of information on the latest developments in the field of biosensors for protein analysis and clinical diagnosis Focuses on biosensors fabricated with nanomaterials and nanotechnology Gives detailed methodologies for designing and fabricating nano-inspired biosensors
Fundamentals Of Hiv Medicine
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Author : William David Hardy
language : en
Publisher: Oxford University Press
Release Date : 2017-04-18
Fundamentals Of Hiv Medicine written by William David Hardy and has been published by Oxford University Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017-04-18 with AIDS (Disease) categories.
Completely updated for 2017, Fundamentals of HIV Medicine is a comprehensive clinical care publication for the treatment of HIV/AIDS. Published by the American Academy of HIV Medicine, the book offers physicians, pharmacists, nurse practitioners, and other care providers the most up-to-date overview of the latest HIV treatments and guidelines plus online access to CME. The online access expires August 2018. Embodying the AAHIVM's commitment to promoting uniform excellence in care of seropositive patients, Fundamentals of HIV Medicine 2017 empowers health professionals to deliver standardized, life-sustaining treatment to the patients who need it most. It will serve as an essential clinical reference and provide valuable career enrichment to users across the spectrum of HIV care, treatment, and prevention.