Combinatorial and Evolutionary Approaches for the Investigation of Receptor-ligand Interactions PDF Download
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Author: Bernhard Michael Schimmele
Publisher:
ISBN:
Category :
Languages : en
Pages : 209
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Author: Bernhard Michael Schimmele
Publisher:
ISBN:
Category :
Languages : en
Pages : 209
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Author: Bernhard Michael Schimmele
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Author: E. C. Hulme
Publisher: Oxford University Press, USA
ISBN:
Category : Medical
Languages : en
Pages : 486
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This is the final volume in a set of 3 books detailing practical methods for the investigation of biochemical receptors. This book deals with the performance and interpretation of receptor-ligand binding studies which are important in many areas of pharmacological and neurochemical research.
Author: Ulrike Koehl
Publisher: Frontiers Media SA
ISBN: 2889456633
Category : Immunologic diseases. Allergy
Languages : en
Pages : 407
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Book Description
Recognition and killing of aberrant, infected or tumor targets by Natural Killer (NK) cells is mediated by positive signals transduced by activating receptors upon engagement of ligands on target surface. These stimulatory pathways are counterbalanced by inhibitory receptors that raise NK cell activation threshold through negative antagonist signals. While regulatory effects are necessary for physiologic control of autoimmune aggression, they may restrain the ability of NK cells to activate against disease. Overcoming this barrier to immune surveillance, multiple approaches to enhance NK-mediated responses are being investigated since two decades. Propelled by considerable advances in the understanding of NK cell biology, these studies are critical for effective translation of NK-based immunotherapy principles into the clinic. In humans, dominant inhibitory signals are transduced by Killer Immunoglobulin Like Receptors (KIR) recognizing cognate HLA class I on target cells. Conversely, KIR recognition of “missing self-HLA” - due to HLA loss or HLA/ KIR mismatch - triggers NK-mediated tumor rejection. Initially observed in murine transplant models, these antitumor effects were later found to have important implications for the clinical outcome of haplotype-mismatched stemcell transplantation. Here, donor NK subsets protect against acute myeloid leukemia (AML) relapse through missing self recognition of donor HLA-C allele groups (C1 or C2) and/or Bw4 epitope. These studies were subsequently extended by trials investigating the antileukemia effects of adoptively transferred haplotype-mismatched NK cells in non-transplant settings. Other mechanisms have been found to induce clinically relevant NK cell alloreactivity in transplantation, e.g., post-reconstitution functional reversal of anergic NK cells. More recently, activating KIR came into the spotlight for their potential ability to directly activate donor NK cells through in vivo recognition of HLA or other ligands. Novel therapeutic monoclonal antibodies (mAb) may optimize NK-mediated effects. Examples include obinutuzumab (GA101), a glyco-engineered anti-CD20 mAb with increased affinity for the FcγRIIIA receptor, enhancing antibody-dependent cellular cytotoxicity; lirilumab (IPH2102), a first-in-class NK-specific checkpoint inhibitor, blocking the interaction between the major KIR and cognate HLA-C antigens; and elotuzumab (HuLuc63), a humanized monoclonal antibody specific for SLAMF7, whose anti-myeloma therapeutic effects are partly due to direct activation of SLAMF7-expressing NK cells. In addition to conventional antibodies, NK cell-targeted bispecific (BiKEs) and trispecific (TriKEs) killer engagers have also been developed. These proteins elicit potent effector functions by binding target ligands (e.g., CD19, CD22, CD30, CD133, HLA class II, EGFR) on one arm and NK receptors on the other. An additional innovative approach to direct NK cell activity is genetic reprogramming with chimeric antigen receptors (CAR). To date, primary NK cells and the NK92 cell line have been engineered with CAR specific for antigens expressed on multiple tumors. Encouraging preclinical results warrant further development of this approach. This Research Topic welcomes contributions addressing mechanisms of NK-mediated activation in response to disease as well as past and contemporary strategies to enhance NK mediated reactivity through control of the interactions between NK receptors and their ligands.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 54
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Author: Mihalis S. Kariolis
Publisher:
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Category :
Languages : en
Pages :
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Ligand-receptor interactions and the specific molecular recognition events that define them govern many important physiological processes. When these interactions become dysregulated, normal physiology quickly degenerates into disease states. Nowhere is this more evident than in metastatic cancer, where aberrant signaling drives uncontrolled cell growth and systemic dissemination of disease. In spite of much effort, the management of metastatic disease has largely remained an intractable clinical challenge as effective treatment options are limited. Protein-based biologics, which leverage the inherent affinity and specificity of protein-protein interactions, offer an effective strategy for targeting and modulating dysregulated disease pathways in order to bring them under control. In this dissertation, we use combinatorial and rational protein engineering methods to develop receptor-based therapeutics that target Axl, a receptor tyrosine kinase shown to be involved in driving metastasis and disease progression in a wide range of human cancers. Using yeast-surface display and directed evolution, Axl variants were engineered for improved binding to Gas6, Axl's activating ligand. To gain an understanding of the molecular basis of the increased binding, detailed biochemical and structural studies were performed, including solving the structure of a high affinity Axl variant in complex with Gas6. When reformatted for in vivo applications, the engineered Axl decoy receptors were found to have apparent affinities to Gas6 as low as 93 fM, which are among some of the strongest protein-protein interactions ever reported. Importantly, when tested in a panel of aggressive mouse models of metastatic disease, the engineered decoy receptors showed significant efficacy, reducing metastatic disease by up to 95%. Collectively, these results validate Axl as a therapeutic target in metastatic disease and highlight the potential clinical value of the engineered Axl decoy receptors as novel anti-metastatic therapies.
Author: Matthew Joseph Styles
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Many common Gram-negative bacteria, including important human pathogens, utilize small molecule signals (N-acyl-L-homoserine lactones, or AHLs) and cognate receptors (LuxR-type receptors) to control group phenotypes, such as virulence factor production, using a cell-to-cell signaling process called quorum sensing (QS). AHLs bind to LuxR-type receptors at high cell densities, which activates a series of macromolecular interactions that lead to altered expression of QS-regulated genes. QS has attracted significant recent attention as a target to block infections in humans, and numerous chemical biology approaches have been aimed towards disrupting this communication process in order to attenuate bacterial virulence. Small molecules that selectively target LuxR-type receptors represent one such approach. To develop these chemical tools, we must significantly expand our understanding of LuxR-type receptor:ligand interactions. These receptors have proven challenging targets for biophysical investigation, especially in the presence of compounds that antagonize receptor activity. This thesis focuses on the development of methods for characterizing LuxR-type receptor:ligand interactions using a combination of chemical biology, biochemical, and biophysical approaches.We began by identifying and developing structure-activity relationships for chemical probes capable of agonizing and antagonizing the orphan LuxR-type QS receptor SdiA in Salmonella and E. coli, characterizing the mechanism of action for a covalent inhibitor, and demonstrating the ability of this inhibitor to interfere with an infection-related phenotype (acid resistance). We next developed a FoÌ8rster Resonance Energy Transfer (FRET) assay to monitor LuxR-type receptor ligand binding in vitro and in intact cells and demonstrated the compatibility of these assays with six LuxR-type receptors. Thereafter, we report a series of biophysical experiments to characterize the interactions of two LuxR-type receptors, QscR from P. aeruginosa and SdiA form E. coli, with a range of small molecules agonists and antagonists. Based on these results, we propose models for the underlying signal transduction mechanism for each receptor. Critically, these results suggest several limitations of standard cell-based reporter assays as proxies for different biophysical parameters, and we provide an alternate path for mechanistic investigations that avoid these limitations. The results presented here provide chemical tools, methods, and conceptual models that will advance chemical approaches to modulate QS.
Author: Yury E. Khudyakov
Publisher: CRC Press
ISBN: 1420007300
Category : Medical
Languages : en
Pages : 588
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An All-Inclusive Review of the Achievements and Trends in the Fast-Growing Protein Engineering Field From humble beginnings like making fire for mere survival, engineering now steadfastly penetrates all aspects of our lives and even life itself at the molecular level. Protein engineering is a molecular biological discipline focused on designing and
Author: Niels Bindslev
Publisher: Co-Action Publishing
ISBN: 9197707104
Category : Chemical models
Languages : en
Pages : 430
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Drug-Acceptor Interactions: Modeling theoretical tools to test and evaluate experimental equilibrium effects suggests novel theoretical tools to test and evaluate drug interactions seen with combinatorial drug therapy. The book provides an in-depth, yet controversial, exploration of existing tools for analysis of dose-response studies at equilibrium or steady state. The book is recommended reading for post-graduate students and researchers engaged in the study of systems biology, networks, and the pharmacodynamics of natural or industrial drugs, as well as for medical clinicians interested in drug application and combinatorial drug therapy. Even people without mathematical skills will be able to follow the pros and cons of reaction schemes and their related distribution equations. Chapter 9 is a hands-on guide for software to plot, fit and analyze one's own data.
Author:
Publisher:
ISBN:
Category : Medicine
Languages : en
Pages : 1828
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