Chemokine Receptors as Drug Targets E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Serie: Methods and Principles in Medicinal Chemistry
• Sprache: Englisch

Seitenzahl: 830

Veröffentlichungsjahr: 2010

Beschreibung

Chemokines are hormone-like signaling molecules secreted by cells to signal infection and guide the immune response. Following a decade of basic chemokine research, the pharmaceutical industry has now begun to exploit this crucial signaling pathway for the development of innovative drugs against AIDS, cancer, neural and autoimmune diseases. Here is the first reference focusing on these novel drug development opportunities. Opening with a general introduction on chemokine function and chemokine receptor biology, the second part covers the known implications of these signaling molecules in human diseases, such as cancer, neural disorders, and viral infection, including AIDS. The third part systematically surveys current drug development efforts at targeting individual chemokine receptors, as well as other chemokine interaction partners, including up-to-date reports from the pharmaceutical industry.

Leseprobe

Contents

Cover

Title Page

Copyright

List of Contributors

Preface

A Personal Foreword

Part One Fundamentals of Chemokines and Chemokine Receptors

1 Structural Aspects of Chemokines and their Interactions with Receptors and Glycosaminoglycans

1.1 Introduction

1.2 Receptor–Ligand Interactions

1.3 Ligand Structure

1.4 Receptor Structure

1.5 Glycosaminoglycan Binding Sites

1.6 Chemokine Analogs–Research Tools and Potential Therapeutics?

Acknowledgments

References

2 Structural Insights for Homology Modeling of Chemokine Receptors

2.1 Introduction

2.2 Chemokines

2.3 The Transmembrane Domain of Chemokine Receptors

2.4 Structural and Functional Role of Internal Water Molecules

2.5 The Structure of the Extracellular Domain of Chemokine Receptors

2.6 The Structure of the Intracellular Domain

2.7 The Binding of Chemokines to Chemokine Receptors

2.8 The Binding of Small-Molecule Ligands to Chemokine Receptors

2.9 Molecular Processes of Receptor Activation

2.10 The Binding of the G Protein

2.11 Receptor Oligomerization

2.12 Conclusions

References

3 Signaling Events Involved in Chemokine-Directed T Lymphocyte Migration

3.1 The Role of GTPases in Chemokine-Directed Lymphocyte Migration

3.2 Class 1 PI3Ks and their Role in Cell Migration: An Overview

3.3 Do PI3K-Dependent Signals Contribute to T Lymphocyte Migration in Response to Chemokines?

3.4 Role of PI3K in T Lymphocyte Homing and Migration In Vivo

3.5 Role of PI3K in Interstitial T Lymphocyte Motility

3.6 Role of Phospholipase C and Protein Kinase C Signaling in Chemokine-Directed T Lymphocyte Migration

3.7 Concluding Remarks and Future Directions

Acknowledgment

References

4 The Atypical Chemokine Receptors

4.1 D6, an Atypical Receptor for Pro-Inflammatory CC Chemokines

4.2 CCX-CKR, an Atypical Receptor for Homeostatic CC Chemokines

4.3 CXCR7: A Second Receptor for CXCL11 and CXCL12 with Critical Roles in Development and Tumorigenesis

4.4 DARC: A Promiscuous Pro-Inflammatory Atypical Chemokine Receptor on Red Blood Cells and Endothelial Cells

4.5 Summary

References

5 Targeting Chemokine Receptor Dimers: Are there Two (or More) to Tango?

5.1 Introduction

5.2 Chemokines and their Receptors

5.3 GPCRs Exist and Function as Dimers

5.4 Detection of GPCR Dimerization

5.5 Chemokine Receptor Dimerization

5.6 Constitutive Versus Induced Chemokine Receptor Dimerization

5.7 Functional Consequences of Chemokine Receptor Dimerization

5.8 (Patho-)Physiological Consequences of Chemokine Receptor Dimerization

Acknowledgment

References

Part Two Chemokine Receptors in Disease

6 Chemokine Receptors in Inflammatory Diseases

6.1 Introduction

6.2 Chemokine Receptors on Inflammatory/Immune Cells

6.3 Chemokine Receptors and Inflammatory Lung Diseases

6.4 Chemokine and Inflammatory Bowel Diseases

6.5 Chemokine Receptors and Rheumatoid Arthritis

6.6 Chemokine Receptors and Atherosclerosis

6.7 Chemokine Receptors in Multiple Sclerosis

6.8 Chemokine Receptors and Psoriasis

6.9 Concluding Remarks

Acknowledgements

References

7 Chemokines and their Receptors in Central Nervous System Disease

7.1 Introduction

7.2 Families of Chemokines

7.3 Chemokine Pharmacology

7.4 Chemokines and Chemokine Receptors: A Complex System

7.5 The Role of the Chemokinergic System in Multiple Sclerosis and Experimental Autoimmune Encephalitis

7.6 The Role of Chemokines in Brain Ischemia

7.7 Chemokines in HIV-Associated Dementia

7.8 Chemokines in Neuropathic Pain

7.9 Conclusions

References

8 Chemokines and Cancer Metastasis

8.1 Introduction

8.2 CXCR4 and CCR7 Receptors Play Special Roles in Cancer Metastasis

8.3 Retrospective Clinical Data Supports a Role for Chemokines in Cancer Metastasis

8.4 How Does the CXCR4/CXCL12 Axis Influence the Development of Metastatic Lesions?

8.5 CXCR4 is a Key Player in the Development of Zebrafish; Role of CXCR7

8.6 The CXCR4/CXCL12 Axis in Stem Cell Homing in the Bone Marrow

8.7 Conclusions and Future Directions

References

9 Constitutively Active Viral Chemokine Receptors: Tools for Immune Subversion and Pathogenesis

9.1 Introduction

9.2 Herpesviruses and Viral Diseases

9.3 Herpesviruses Encode Constitutively Active Viral Chemokine Receptors

9.4 Concluding Remarks

References

Part Three Targeting Chemokine Receptors

10 CCR5 Antagonists in HIV

10.1 Introduction

10.2 CCR5 Antagonist Programs

10.3 Molecular Interactions and Binding Modes of CCR5 Receptor Antagonists

10.4 Resistance to CCR5 Receptor Antagonists

10.5 Outlook

Acknowledgment

References

11 CXCR4 as a Therapeutic Target

11.1 Biology and Physiological Role of CXCR4

11.2 Patho-Physiological Role of CXCR4: Potential as a Therapeutic Target

11.3 Concluding Remarks

Acknowledgments

References

12 Low Molecular Weight CXCR2 Antagonists as Promising Therapeutics

12.1 Introduction

12.2 CXCR2 Ligands and Signal Transduction

12.3 Biological Functions

12.4 CXCR2 in Inflammatory Disorders

12.5 Low Molecular Weight CXCR2 Antagonists

12.6 Challenges and Future Perspectives

Acknowledgments

References

13 Therapeutic Targeting of the CXCR3 Receptor

13.1 The CXCR3 Receptor

13.2 CXCR3 as a Potential Drug Target

13.3 The Development of CXCR3 Antagonists

13.4 CXCR3 Antagonists in Disease Models and in the Clinic

13.5 Conclusion and Outlook

Acknowledgments

References

14 Targeting CCR1

14.1 Introduction

14.2 CCR1 as a Drug Target

14.3 CCR1 Antagonists

14.4 Conclusions

References

15 Targeting CCR3

15.1 Introduction

15.2 CCR3 and the Eotaxin Family of Chemokines

15.3 Structure–Function Studies of CCR3 and its Ligands

15.4 CCR3 and its Ligands in the Pathogenesis of Allergic Disease

15.5 Targeting CCR3 Function

15.6 Small-Molecule CCR3 Antagonists with In Vivo Activity

15.7 Summary

References

16 Chemokine Binding Proteins as Therapeutics

16.1 Immune Modulation by Secreted Chemokine Binding Proteins (CKBPs)

16.2 Viral CKBPs (vCKBPs)

16.3 The Schistosoma mansoni CKBP

16.4 Evasins, a Family of CKBPs from Ticks

16.5 Advantages and Limitations of the Use of CKBPs as Therapeutics

Acknowledgments

References

Index

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. Folkers

Editorial Board

H. Buschmann, H. Timmerman, H. van de Waterbeemd, T. Wieland

Previous Volumes of this Series:

Ghosh, Arun K. (Ed.)

Aspartic Acid Proteases as Therapeutic Targets

2010

ISBN: 978-3-527-31811-7

Vol. 45

Ecker, Gerhard F. / Chiba, Peter (Eds.)

Transporters as Drug Carriers

Structure, Function, Substrates

2009

ISBN: 978-3-527-31661-8

Vol. 44

Faller, Bernhard / Urban, Laszlo (Eds.)

Hit and Lead Profiling

Identification and Optimization of Drug-like Molecules

2009

ISBN: 978-3-527-32331-9

Vol. 43

Sippl, Wolfgang / Jung, Manfred (Eds.)

Epigenetic Targets in Drug Discovery

2009

ISBN: 978-3-527-32355-5

Vol. 42

Todeschini, Roberto / Consonni, Viviana

Molecular Descriptors for Chemoinformatics

Volume I: Alphabetical Listing / Volume II: Appendices, References

2009

ISBN: 978-3-527-31852-0

Vol. 41

van de Waterbeemd, Han / Testa, Bernard (Eds.)

Drug Bioavailability

Estimation of Solubility, Permeability, Absorption and Bioavailability Second, Completely Revised Edition

2008

ISBN: 978-3-527-32051-6

Vol. 40

Ottow, Eckhard / Weinmann, Hilmar (Eds.)

Nuclear Receptors as Drug Targets

2008

ISBN: 978-3-527-31872-8

Vol. 39

Vaz, Roy J. / Klabunde, Thomas (Eds.)

Antitargets

Prediction and Prevention of Drug Side Effects

2008

ISBN: 978-3-527-31821-6

Vol. 38

Mannhold, Raimund (Ed.)

Molecular Drug Properties

Measurement and Prediction

2007

ISBN: 978-3-527-31755-4

Vol. 37

Wanner, Klaus / Höfner, Georg (Eds.)

Mass Spectrometry in Medicinal Chemistry

Applications in Drug Discovery

2007

ISBN: 978-3-527-31456-0

Vol. 36

Series Editors

Prof. Dr. Raimund Mannhold

Molecular Drug Research Group

Heinrich-Heine-Universität

Universitätsstrasse 1

40225 Düsseldorf

Germany

[email protected]

Prof. Dr. Hugo Kubinyi

Donnersbergstrasse 9

67256 Weisenheim am Sand

Germany

[email protected]

Prof. Dr. Gerd Folkers

Collegium Helveticum

STW/ETH Zurich

8092 Zurich

Switzerland

[email protected]

Volume Editors

Prof. Dr. Martine J. Smit

VU University Amsterdam

Faculty of Sciences

Department of Medicinal Chemistry

Leiden/Amsterdam Center for Drug Research

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

Dr. Sergio A. Lira

Mount Sinai School of Medicine

Immunology Institute

New York, NY 10029-6574

USA

Prof. Dr. Rob Leurs

VU University Amsterdam

Faculty of Sciences

Department of Medicinal Chemistry

Leiden/Amsterdam Center for Drug Research

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

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ISBN: 978-3-527-32118-6

List of Contributors

Antonio Alcami

Consejo Superior de Investigaciones

Científicas–Universidad Autónoma

de Madrid

Centro de Biología Molecular Severo

Ochoa

Nicolás Cabrera 1, Cantoblanco

28049 Madrid

Spain

and

University of Cambridge

Department of Medicine

Addenbrooke's Hospital

Hills Road

Cambridge CB2 2QQ

UK

Ali Alejo

Instituto Nacional de Investigaciones

Agrarias

Centro de Investigación en Sanidad

Animal

Valdeolmos

Madrid

Spain

Françoise Bachelerie

INSERM U819

Institut Pasteur

Unité Pathogénie Virale

25-28 Rue du Dr Roux

75724 Paris Cedex 15

France

Christopher G. Barber

Sandwich Laboratories

Pfizer Global Research and Development

Pain Therapeutics Chemistry Research

Ramsgate Road

Kent CT13 9NJ

UK

Knut Biber

University Medical Center für Psychiatry

Hauptstraße 8

Freiburg

Germany

Hendrikus W. G. M. Boddeke

University Medical Center Groningen

Medical Physiology Section

Department of Neuroscience

Ant. Deusinglaan 1

9712 AV Groningen

The Netherlands

Gerold Bongers

Mount Sinai School of Medicine

Immunology Institute

New York, NY 10029-6574

USA

Saskia Braber

Utrecht University

Faculty of Sciences

Utrecht Institute for Pharamaceutical Sciences

Division of Pharmacology and Pathophysiology

PO Box 80082

3508 TB Utrecht

The Netherlands

Mercedes Campillo

Universitat Autònoma de Barcelona

Facultat de Medicina

Unitat de Bioestadística

Laboratori de Medicina Computacional

08193 Bellaterra

Spain

Ken Y.C. Chow

INSERM U819

Institut Pasteur

Unité Pathogénie Virale

25-28 Rue du Dr Roux

75724 Paris Cedex 15

France

and

VU University Amsterdam

Department of Medicinal Chemistry

Leiden/Amsterdam Center of Drug Research

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

Arnau Cordomí

Universitat Autònoma de Barcelona

Facultat de Medicina

Unitat de Bioestadística

Laboratori de Medicina Computacional

08193 Bellaterra

Spain

Iwan J.P. de Esch

VU University Amsterdam

Faculty of Sciences

Division of Medicinal Chemistry

Leiden/Amsterdam Center for Drug Research

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

Petra de Kruijf

VU University Amsterdam

Department of Medicinal Chemistry

Leiden/Amsterdam Center of Drug Research

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

Xavier Deupi

Universitat Autònoma de Barcelona

Facultat de Medicina

Unitat de Bioestadística

Laboratori de Medicina Computacional

08193 Bellaterra

Spain

Cedric Govaerts

Université Libre de Bruxelles

Structural Biology and Bioinformatics Center

Department of Structure and Function of Biological Membranes

Brussels

Belgium

Gerard J. Graham

University of Glasgow

Glasgow Biomedical Research Centre

Division of Immunology, Infection and Inflammation

120 University Place

Glasgow G12 8TA

UK

Damon Hamel

University of California San Diego

Skaggs School of Pharmacy and Pharmaceutical Sciences

9500 Gilman Drive

La Jolla, CA 92093-0684

USA

Tracy M. Handel

University of California San Diego

Skaggs School of Pharmacy and Pharmaceutical Sciences

9500 Gilman Drive

La Jolla, CA 92093-0684

USA

Richard Horuk

University of California Davis

Department of Pharmacology

451, Health Sciences Drive

Davis, CA 95616

USA

Pim Koelink

Utrecht University

Faculty of Sciences

Utrecht Institute for Pharamaceutical Sciences

Division of Pharmacology and Pathophysiology

PO Box 80082

3508 TB Utrecht

The Netherlands

Aletta D. Kraneveld

Utrecht University

Faculty of Sciences

Utrecht Institute for Pharamaceutical Sciences

Division of Pharmacology and Pathophysiology

PO Box 80082

3508 TB Utrecht

The Netherlands

Rob Leurs

VU University Amsterdam

Faculty of Sciences

Department of Medicinal Chemistry

Leiden/Amsterdam Center for Drug Research

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

Sergio A. Lira

Mount Sinai School of Medicine

Immunology Institute

New York, NY 10029-6574

USA

David Maussang

VU University Amsterdam

Faculty of Sciences

Department of Medicinal Chemistry

Leiden/Amsterdam Center for Drug Research

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

Katsuhiro Mihara

Schering–Plough Research Institute

Molenstraat 110, P.O. Box 20

5340 BH Oss

The Netherlands

Robert J. B. Nibbs

University of Glasgow

Glasgow Biomedical Research Centre

Division of Immunology, Infection and Inflammation

120 University Place

Glasgow G12 8TA

UK

Saskia Nijmeijer

VU University Amsterdam

Faculty of Sciences

Department of Medicinal Chemistry

Leiden/Amsterdam Center for Drug Research

De Boeleaan 1083

1081 HV Amsterdam

The Netherlands

Saskia Overbeek

Utrecht University

Faculty of Sciences

Utrecht Institute for Pharamaceutical Sciences

Division of Pharmacology and Pathophysiology

PO Box 80082

3508 TB Utrecht

The Netherlands

Leonardo Pardo

Universitat Autònoma de Barcelona

Facultat de Medicina

Unitat de Bioestadística

Laboratori de Medicina Computacional

08193 Bellaterra

Spain

Marc Parmentier

Université Libre de Bruxelles

Institut de Recherche Interdisciplinaire

en Biologie Humaine et Moléculaire

Campus Erasme, 808 Route de Lennik

1070 Brussels

Belgium

James Edward Pease

Imperial College London

Faculty of Medicine

National Heart and Lung Institute

Leukocyte Biology Section

Sir Alexander Fleming Building

South Kensington Campus

London SW7 2AZ

UK

Amanda E. I. Proudfoot

Merck Serono SA

Geneva Research Centre

9 Chemin des Mines

1202 Geneva

Switzerland

David C. Pryde

Sandwich Laboratories

Pfizer Global Research and Development

AntiVirals Chemistry Research

Ramsgate Road

Kent CT13 9NJ

UK

India Severin

Merck Serono SA

Geneva Research Centre

9 Chemin des Mines

1202 Geneva

Switzerland

Mark D. Singh

University of Glasgow

Glasgow Biomedical Research Centre

Division of Immunology, Infection and Inflammation

120 University Place

Glasgow G12 8TA

UK

Martine J. Smit

VU University Amsterdam

Faculty of Sciences

Division of Medicinal Chemistry

Leiden/Amsterdam Center for Drug Research

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

Henry F. Vischer

VU University Amsterdam

Faculty of Sciences

Department of Medicinal Chemistry

Leiden/Amsterdam Center for Drug Research

De Boeleaan 1083

1081 HV Amsterdam

The Netherlands

Stephen G. Ward

University of Bath

Department of Pharmacy and Pharmacology

Claverton Down

Bath BA2 7AY

UK

Jac Wijkmans

Schering–Plough Research Institute

Molenstraat 110, P.O. Box 20

5340 BH Oss

The Netherlands

Maikel Wijtmans

VU University Amsterdam

Faculty of Sciences

Department of Medicinal Chemistry

Leiden/Amsterdam Center for Drug Research

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

Albert Zlotnik

University of California at Irvine

Institute for Immunology

Department of Physiology and Biophysics

3034 Hewitt Hall, Bldg. 843

Irvine, CA 92697-4120

USA

Preface

This volume is dedicated to the family of chemokine receptors, belonging to the class of G protein-coupled receptors (GPCRs). Chemokine receptors are primarily expressed on leukocytes, but are also present on cells of nonhematopoietic origin, such as endothelial cells and neurons. The chemokine receptor system is known to orchestrate various aspects of the immune system but also appears to control a variety of physiological processes. Excessive expression of chemokines and chemokine receptors and deregulated chemokine receptor function results in various disease states, including chronic inflammatory and vascular diseases and oncogenesis. Viruses have also taken advantage of the chemokine receptor system, indicating a role of this class of receptors in viral infection. The chemokine receptors CCR5 and CXCR4 are the two major co-receptors for HIV-1 entry into host cells. The pox- and herpesviruses express chemokines, chemokine-binding proteins and/or chemokine receptors, which may contribute to viral pathogenesis.

Since GPCRs are one of the most favored drug targets and the role of chemokine receptors in disease is becoming apparent, chemokine receptors are considered prime targets in drug research. The first successful small molecule targeting the chemokine receptor system was the CCR5 antagonist, for the prevention of HIV infection, approved by the FDA in 2007. The second small molecule (a CXCR4 antagonist) was approved by the FDA at the end of 2008 for hematopoietic stem cell mobilization. In the mean time the understanding of the chemokine receptor system is growing and several promising drugs are currently being tested in late-stage clinical trials.

The present volume by Martine Smit, Sergio Lira, and Rob Leurs is organized into three main sections, addressing fundamental, pathophysiological and drug discovery aspects of chemokine receptors. Following the philosophy of this series, authors from the different chapters come from academic institutions and pharmaceutical industry, fostering an active exchange between these two communities. The first section introduces the field of chemokines and their receptors, particularly referring to structural aspects. The second section focuses on the relevance of human and viral chemokine receptors in various diseases, such as inflammation, CNS diseases and cancer. The final section gives an overview of the currently available chemokine receptor ligands and their therapeutic impact. Six different chemokine receptor subtypes are particularly referred to. The last chapter comments on chemokine-binding proteins as therapeutics.

The series editors thank Martine Smit, Sergio Lira, and Rob Leurs for their enthusiasm to organize this volume and to work with such a fine selection of authors. We also express our thanks to Nicola Oberbeckmann-Winter, Waltraud Wüst, and Frank Weinreich from Wiley-VCH for their valuable contributions to this project and to the entire series.

Raimund Mannhold, Düsseldorf

Hugo Kubinyi, Weisenheim am Sand

Gerd Folkers, Zürich

August 2010

A Personal Foreword

The chemokine receptors, belonging to the family of G protein-coupled receptors are considered attractive targets for therapeutic intervention. Chemokines and their receptors play a prominent role in the development, homeostasis and activation of leukocytes in the innate and adapative immune system. Expression of chemokine receptors is not confined to leukocytes but is also apparent on cells of nonhematopoietic origin such as endothelial cells and neurons. Their excessive activity or dysfunction, however, is associated with the establishment of inflammation and diseases such as multiple sclerosis, inflammatory bowel disorder, arthritis and atherosclerosis. There is growing evidence that chemokine receptors play a role in cancer, including cancer metastasis and angiogenesis. Virus-encoded chemokines, chemokine receptors and chemokine scavengers have been identified, underscoring the importance of the chemokine system in viral pathogenesis. Besides chemokine receptors, CCR5 and CXCR4 have been shown to play profound roles in HIV pathogenesis through their ability to act as co-receptors for viral entry. This has led to the first approval by the FDA for a chemokine receptor antagonist for the prevention of HIV infection.

In the past decades much insight has been obtained on the structure of chemokines, the identification of their receptors and the mechanisms underlying the complex biologies in which they participate. This volume addresses the fundamental, pathophysiological and drug discovery aspects of chemokine receptors. The first part includes chapters that describe the fundamental aspects of chemokines and chemokine receptors. First, overviews are provided of the structure of chemokines and their receptors in relation to their biology and structural insights for homology modelling of chemokine receptors. The latest insights into the molecular mechanisms underlying chemokine-directed migration, a key event induced upon chemokine receptor activation, are presented. Besides the “classical” chemokine receptors, the biochemistry and biology of “atypical” chemokine receptors are explored and outlined. Last, the functional consequences and implications of homo/hetero dimerization of chemokine receptors are discussed.

The second part of this volume includes chapters that provide a comprehensive description of the role of the chemokine receptors in various diseases. The roles of various chemokines and chemokine receptors in chronic inflammatory diseases are outlined, including COPD, IBD, atherosclerosis and psoriasis. Thereafter, the role of the chemokine system in neurodegenerative diseases, including MS and EAE, brain ischemia and HIV-associated dementia, and in neuropathic pain is addressed. In addition, the latest insights into the role of chemokines and chemokine receptors in cancer metastasis are provided and potential roles of virus-encoded chemokine receptors are discussed. The final chapters discuss in detail different chemokine receptors, including CCR5, CXCR4, CXCR2, CXCR3, CCR1 and CCR3, as well as chemokine-binding proteins, with respect to therapeutical targeting and/or drug development.

Finally, we want to thank all authors of the different chapters from both academic institutions and the pharmaceutical industry for their valuable contributions. In addition, we want to acknowledge the pleasant collaboration with the series editor Dr. Raimund Mannhold as well as Dr. Frank Weinreich and Dr. Nicola Oberbeckmann-Winter from Wiley-VCH during the editing of this volume.

Martine Smit, Amsterdam

Sergio Lira, New York

Rob Leurs, Amsterdam

July 2010

Part One

Fundamentals of Chemokines and Chemokine Receptors

1

Structural Aspects of Chemokines and their Interactions with Receptors and Glycosaminoglycans

Amanda E. I. Proudfoot, India Severin, Damon Hamel, and Tracy M. Handel

1.1 Introduction

Chemokines are a large subfamily of cytokines (∼50 in humans) that can be distinguished from other cytokines due to several features. They share a common biological activity, which is the control of the directional migration of leukocytes, hence their name, chemoattractant cytokines. They are all small proteins (approx. 8 kDa) that are highly basic, with two exceptions (MIP-1α, MIP-1β). Also, they have a highly conserved monomeric fold, constrained by 1–3 disulfides which are formed from a conserved pattern of cysteine residues (the majority of chemokines have four cysteines). The pattern of cysteine residues is used as the basis of their division into subclasses and for their nomenclature. The first class, referred to as CXC or α-chemokines, have a single residue between the first N-terminal Cys residues, whereas in the CC class, or β-chemokines, these two Cys residues are adjacent. While most chemokines have two disulfides, the CC subclass also has three members that contain three. Subsequent to the CC and CXC families, two additional subclasses were identified, the CX3C subclass [1, 2], which has three amino acids separating the N-terminal Cys pair, and the C subclass, which has a single disulfide.

The first chemokine, PF-4, was identified in 1977 [3] but it was not for almost a decade that other members of the family started to emerge, with the discovery of the proinflammatory chemokines: IP-10 was identified in 1985 as a protein showing homology to PF4 [4], while IL-8 and the MIP-1 proteins were isolated in the late 1980s as active protein from tissues or culture supernatants. The neutrophil chemoattractant, IL-8, was purified from culture supernatant of stimulated blood monocytes [5] and the monocyte chemoattractants MIP-1α and MIP-1β were purified from LPS-stimulated mouse macrophages [6]. The primary amino acid sequence of these chemokines rapidly led to the identification of the highly conserved four-cysteine motif described above and also allowed their classification into the two principal subclasses. The number of chemokines then grew rapidly through homology cloning using the conserved motifs, but the real explosion in the identification of members came from EST database searches [7]. Initially, chemokines were given names usually associated with their activity; for example, the MIP-1 proteins were discovered as “macrophage inflammatory proteins”. Similarly, PF-4 (platelet factor IV) was a factor produced from platelets. However, since members of the family were often identified concomitantly by different laboratories resulting in different names, a systemic nomenclature was introduced in 2000 in order to introduce harmonization [8]. In this nomenclature, the ligands are named according to subclass (CC, CXC, C, CX3C) followed by L for ligand and a number. Under this nomenclature IL-8 became CXCL8 while MIP-1α became CCL3. This nomenclature was created for human chemokines based on their genomic localization, but was rapidly “pirated” for the mouse chemokines, since even prestigious journals insisted that the new nomenclature be applied to the mouse chemokines! Interestingly certain chemokines are not found in both the human and mouse systems. For instance CXCL8 does not exist in the mouse, and the equivalent of several mouse chemokines such as lungkine and MCP-5 (CXCL15 and CCL12, respectively), have not been identified in humans (as shown in ), which shows the old and new nomenclatures for human chemokines. In the rest of the chapter, we refer to chemokines by their new nomenclature.