Biotherapeutics: Recent Developments using Chemical and Molecular Biology (RSC Drug Discovery, 36) - Hardcover

Hardcover

ISBN 10: 1849736014 ISBN 13: 9781849736015

Verlag: Royal Society of Chemistry, 2013

Inhaltsangabe

This book illustrates the successful partnership of chemistry and biology to advance successful biotherapeutic modalities. Molecular design to create function is common to both chemical and molecular biology, and this text highlights recent developments from these disciplines that have delivered drugs, clinical candidates or significantly advanced biotherapeutic approaches.

Biotherapeutics are often considered to be beyond the reach of the medicinal chemist, but this book demonstrates that chemistry has an essential role in the future success of this area, by explaining and describing the chemical biology technologies that underpin specific therapeutic advances and demonstrating the unique value of molecular design and understanding.

Covering topics such as selective protein modification, immunopharmacotherapy, chemically programmed vaccinations, nanobodies and antibodies, this book provides essential reading for medicinal and pharmaceutical chemists working in both industry and academia.

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This book will illustrate the successful partnership of chemistry and biology to advance successful biotherapeutic modalities. Molecular design to create function is common to both chemical and molecular biology, and this text will highlight recent developments from these disciplines that have delivered drugs, clinical candidates or significantly advanced biotherapeutic approaches.

Biotherapeutics are often considered to be beyond the reach of the medicinal chemist, but this book demonstrates that chemistry has an essential role in the future success of this area, by explaining and describing the chemical biology technologies that underpin specific therapeutic advances and demonstrating the unique value of molecular design and understanding.

Covering topics such as selective protein modification, immunopharmacotherapy, chemically programmed vaccinations, nanobodies and antibodies, this book will provide essential reading for medicinal and pharmaceutical chemists working in both industry and academia.

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Biotherapeutics

Recent Developments using Chemical and Molecular Biology

By Lyn H. Jones, Andrew J. McKnight

The Royal Society of Chemistry

Copyright © 2013 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-601-5

Contents

Chapter 1 Synthetic Immunology Thihan R. Padukkavidana, Patrick J. MCEnaney and David A. Spiegel, 1, 
Chapter 2 Immunopharmacotherapy for Nicotine Addiction Jonathan W. Lockner and Kim D. Janda, 36, 
Chapter 3 Carbohydrate Vaccines Benjamin Schumann, Chakkumkal Anish, Claney L. Pereira and Peter H. Seeberger, 68, 
Chapter 4 Generation and Maturation of Therapeutic Antibodies via In Vitro Somatic Hypermutation David J. King, 105, 
Chapter 5 Synthetic Protein Biologics Benjamin G. Davis, 130, 
Chapter 6 Recent Advances in Antibody–Drug Conjugates Edmund I. Graziani and L. Nathan Tumey, 145, 
Chapter 7 MicroRNA Biotherapeutics: Key Challenges from a Drug Development Perspective Sterghios Athanasios Moschos, 176, 
Chapter 8 Novel Therapeutic Agents from Bacterial Toxins John A. Chaddock, 224, 
Chapter 9 Phage Selection of Mono- and Bicyclic Peptide Ligands Shiyu Chen and Christian Heinis, 241, 
Chapter 10 Chemical Approaches for Localization, Characterization and Mimicry of Peptide Epitopes Paul R. Werkhoven and Rob M.J. Liskamp, 263, 
Chapter 11 Cystine-Knot Micro-Proteins Bill Eldridge, Simon Robins and Duncan McGregor, 285, 
Subject Index, 298, 

CHAPTER 1

Synthetic Immunology

THIHAN R. PADUKKAVIDANA, PATRICK J. MCENANEY AND DAVID A. SPIEGEL

1.1 Introduction and Scope

The field of immunology has become increasingly lucid at the level of atoms and molecules. Owing also to advances in synthetic chemistry, the rational design and construction of synthetic systems that perform complex immunological functions – an area termed synthetic immunology – has come within reach. Here we will highlight one facet of synthetic immunology concerned with the development of low-molecular weight ("small"), synthetic molecules that are capable of functionally mimicking biological molecules. It is important to note at the outset that this article does not aim to be comprehensive in scope. At the expense of being all-inclusive, we focus on several specific contributions, which highlight how advances in immunology and chemistry have proven mutually complementary. We have divided this chapter into four subsections: (1) synthetic ligands for pattern recognition receptors, including toll-like receptors (TLRs), NOD-like receptors (NLRs), nuclear family receptors and C-type lectins, (2) synthetic molecules that modulate the complement system, (3) synthetic systems for controlling cell–cell communication, including chemokine/cytokine mimetics, and (4) synthetic ligands for modulating adaptive immune processes, including T-cell and B-cell functions.

We regret not being able to cover all of the exciting developments that might be classified into the area of Synthetic Immunology. Such areas include: synthetic vaccine development, as this topic is covered elsewhere in this book; synthetic modulators of cellular signaling processes, as the functions of such molecules extend beyond the immune system; protein-based and cellular immunotherapies, including therapeutic monoclonal antibodies; immunomodulator strategies involving nanoparticles or virus-like particles; DNA- and RNA-based therapeutics; and strategies for controlling cellular differentiation. Lead references to each of these areas are provided for interested readers.

It is our hope that this chapter will serve as a broad-based introduction for biomedical scientists, including chemists interested in extending their activities into the immunological realm, as well as immunologists looking to learn about how modern synthetic chemistry can enhance fundamental biological understanding. Ultimately, we believe that the intellectual perspective residing at the interface between synthetic chemistry and immunology will enable scientific advances that were never before thought possible, thus proving critical to the furtherance of basic biomedical research and patient care.

1.2 Synthetic Ligands for Pattern Recognition Receptors (PRRs)

Pattern recognition receptors (PRRs) are a diverse class of proteins that function canonically as part of the innate immune response. These receptors recognize pathogen-associated molecular patterns (PAMPs), which are widely conserved, repeating motifs found within pathogens and not within hosts, as well as damage-associated molecular patterns (DAMPs), which are host-derived molecules that arise from tissue damage. Improper activation of these receptors has been shown to cause hyper-inflammatory disease states, and extensive research efforts have focused on identifying PRR antagonists. Such developments have been reviewed elsewhere. In this section we discuss a few select examples of molecules that functionally mimic the natural ligands of PRRs.

1.2.1 Synthetic Mimics of TLR Ligands

Toll-like receptors (TLRs) were originally discovered as important receptors for Drosophila melanogaster embryonic development, and were later found to play a critical role in innate immunity in humans. Extensive research during the past two decades has revealed the TLR superfamily to contain more than ten different family members (TLRs 1–13).

TLR2 is capable of binding various bacterial lipopeptides, as well as self-derived ligands such as high mobility group box 1 (HMGB1) and products of lipid oxidation. Interestingly, TLR2 preferentially forms heterodimers with other TLR members (e.g., TLRs 1 and 6), thus expanding its ligand binding profile. Indeed, synthetic lipopeptide collections, designed to mimic the acylated amino terminus of bacterial lipoproteins, have proven critical to understanding the different adaptor molecules involved in TLR2 function. These studies have led to the understanding that the TLR2 heterodimer formed in response to a given ligand depends both on the arrangement of fatty acyl groups and the sequence of peptide backbones in that ligand. For example, synthetic tri-acylated lipopetpides, such as Pam3CSK4 (Figure 1.1, Panel A, 1), selectively engage the TLR2–TLR1 heterodimer, while di-acylated analogs, such as Pam2CSK4 (2), bind both TLR2–TLR1 and TLR2–TLR6 heterodimers. Modification of the peptide backbone in Pam2CSK4 with the decapeptide GDPKHSPKSF provides fibroblast-stimulating lipopeptide-1-(FSL-1, 3), which is selective for the TLR2–TLR6 complex. A crystal structure of the TLR1–TLR2–lipopeptide provides some insight into the molecular origin of this ligand-dependence. Furthermore, the specific TLR2 heterodimer formed in response to ligand stimulation can have a significant effect on downstream biological outputs. For example, synthetic ligands that induce TLR2–TLR1 heterodimer formation (e.g., Pam3CSK4) have been shown to enhance regulatory T-cell (Treg) proliferation to a larger extent than those leading to other heterodimeric TLR2 complexes. Conversely, a small molecule inhibitor of the TLR2–TLR1 complex was recently discovered through a cell-based high-throughput small molecule screen. Efforts to expand the repertoire of TLR2-targeted compounds offer hope of providing chemical insights into immunomodulatory functions, while also delivering useful lead molecules for studying pathogen recognition, cancer progression, and other disease-relevant biological processes.

TLR4 recognizes...

Details zur Ausgabe

• Verlag: Royal Society of Chemistry
• Erscheinungsdatum: 2013
• Sprache: Englisch
• ISBN 10: 1849736014
• ISBN 13: 9781849736015
• Einband: Gebundene Ausgabe
• Anzahl der Seiten: 316
• Herausgeber: Jones Lyn, McKnight Andrew J.
• Kontakt zum Hersteller: Nicht verfügbar
• Verantwortliche Person: Nicht verfügbar