Antimicrobial Peptides 2ND EDITION This page intentionally left blank Antimicrobial Peptides Discovery, Design and Novel Therapeutic Strategies 2ND EDITION Edited by Guangshun Wang University of Nebraska Medical Center, Omaha, Nebraska, USA CABI is a trading name of CAB International CABI CABI Nosworthy Way 745 Atlantic Avenue Wallingford 8th Floor Oxfordshire OX10 8DE Boston, MA 02111 UK USA Tel: +44 (0)1491 832111 Tel: +1 (617)682-9015 Fax: +44 (0)1491 833508 E-mail: [email protected] E-mail: [email protected] Website: www.cabi.org © CAB International 2017. All rights reserved. No part of this publication may be reproduced in any form or by any means, electronically, mechanically, by photocopying, recording or otherwise, without the prior permission of the copyright owners. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Names: Wang, Guangshun. Title: Antimicrobial peptides : discovery, design and novel therapeutic strategies / editor, Guangshun Wang. Other titles: Antimicrobial peptides (Wang) Description: 2nd edition. | Wallingford, Oxfordshire, UK ; Boston, MA : CABI, [2017] | Includes bibliographical references and index. Identifiers: LCCN 2017016223 (print) | LCCN 2017018723 (ebook) | ISBN 9781786390400 (ePDF) | ISBN 9781786390417 (ePub) | ISBN 9781786390394 (hbk: alk. paper) Subjects: | MESH: Antimicrobial Cationic Peptides | Anti-Infective Agents |Immunity, Innate | Drug Design Classification: LCC RS431.P37 (ebook) | LCC RS431.P37 (print) | NLM QU 68 |DDC 615/.1--dc23 LC record available at https://lccn.loc.gov/2017016223 ISBN: 978 1 78639 039 4 (hardback) 978 1 78639 040 0 (e-book) 978 1 78639 041 7 (e-pub) Commissioning editor: Rachael Russell Editorial assistant: Emma McCann Production editor: Alan Worth Typeset by Typeset by AMA DataSet Ltd, Preston, UK Printed and bound in the UK by CPI Group (UK) Ltd, Croydon, CR0 4YY Contents Contributors xi Preface xiii Introduction to the Second Edition xvii Michael Zasloff Part i: overview of antimicrobial PePtides 1 Discovery, Classification and Functional Diversity of Antimicrobial Peptides 1 Guangshun Wang 1.1 A Brief Timeline of Discovery 2 1.2 Nomenclature of Antimicrobial Peptides 5 1.3 Classification of Antimicrobial Peptides 6 1.3.1 Source kingdoms 6 1.3.2 Peptide synthesis machinery 8 1.3.3 Chemical modifications 8 1.3.4 Peptide charge, length and hydrophobic content 9 1.3.5 Three-dimensional structures 10 1.3.6 Unified peptide classification based on polypeptide chain bonding patterns 10 1.3.7 Peptide binding targets and mechanisms of action 11 1.4 Functional Diversity and Terminology of Antimicrobial Peptides 11 1.4.1 Antimicrobial peptides 11 1.4.2 Host defence peptides 13 1.4.3 Innate immune peptides 13 1.5 Concluding Remarks 14 Part ii: natural temPlates for PePtide engineering 2 Structural and Functional Diversity of Cathelicidins 20 Alessandro Tossi, Barbara Skerlavaj, Francesca D’Este and Renato Gennaro v vi Contents 2.1 Introduction 20 2.2 Discovery of Cathelicidins 21 2.3 Evolution, Structural Diversity and Features of the Proregion 26 2.3.1 Evolution 26 2.3.2 Structural diversity 26 2.3.3 Features of the proregion 29 2.4 Expression and Processing 30 2.5 Structure-dependent Mode of Action 31 2.6 Pleiotropic Roles of Cathelicidins in Host Defence and Potential Applications 35 2.7 Conclusions 37 3 Disulfide-linked Defensins 49 Monique L. van Hoek 3.1 Overview 49 3.1.1 Introduction to disulfide-linked defensins 49 3.1.2 Mechanisms of action 50 3.1.3 Structural features of defensins 50 3.2 Vertebrate Defensins 51 3.2.1 β-defensins 51 3.2.2 α-defensins 57 3.2.3 θ-defensins 59 3.3 Arthropod Defensins 59 3.3.1 Insect defensins 59 3.3.2 Therapeutic potential of insect defensins 61 3.3.3 Antiparasitic activity of arthropod defensin peptides 61 3.3.4 Horseshoe crab and oyster big-defensins 61 3.4 Plant Defensins 62 3.5 When is a Disulfide-linked Antimicrobial Peptide not a Defensin? 62 3.6 Therapeutic Potential of Synthetic Disulfide-linked Defensin Peptides 63 3.7 Summary 63 3.7.1 Phylogenetic diversity of defensin gene expression 63 3.7.2 Defensin activity 63 4 Lantibiotics: Bioengineering and Applications 72 Brian Healy and Paul D. Cotter 4.1 Lantibiotics: Background, Structure, Mode of Action and Classification 72 4.2 Lantibiotics as Clinical and Chemotherapeutic Agents 75 4.3 Lantibiotics as Biopreservatives 76 4.4 Lantibiotic Bioengineering and Synthetic Engineering 77 4.4.1 In vivo engineering 77 4.4.2 (Semi)Synthetic engineering 79 4.5 Future Outlook and Conclusion 80 Part iii: exPanding PePtide sPace: combinatorial library, genome-based Prediction and de novo design 5 Discovery of Novel Antimicrobial Peptides Using Combinatorial Chemistry and High-throughput Screening 86 Charles G. Starr and William C. Wimley 5.1 The Interfacial Activity Model of AMP Activity 86 5.2 Combinatorial Chemistry Methods 87 Contents vii 5.2.1 Overview of library synthesis 87 5.2.2 Non-indexed methods 88 5.2.3 Indexed methods 90 5.3 High-throughput Screening 91 5.3.1 Biological assays 91 5.3.2 Non-biological assays 94 5.3.3 Parallel screening for selection of discrete characteristics 94 5.4 Accomplishments 96 5.4.1 Beyond high-throughput screening 97 5.5 Future Directions 98 6 Prediction and Design of Antimicrobial Peptides: Methods and Applications to Genomes and Proteomes 101 Guangshun Wang 6.1 Antimicrobial Peptide Prediction 102 6.1.1 Prediction based on mature peptides 103 6.1.2 Prediction based on highly conserved propeptide sequences 105 6.1.3 Prediction based on both propeptides and mature peptides 106 6.1.4 Prediction based on the processing enzymes or transporters 106 6.1.5 Genomic context-based prediction 107 6.1.6 Applications to genomes and proteomes 107 6.2 Database-aided Peptide Design and Improvement 108 6.2.1 Anti-HIV and anti-MRSA peptide screening 108 6.2.2 Sequence shuffling and the combinatorial library approach 110 6.2.3 The hybrid approach and grammar-based peptide design 110 6.2.4 De novo and database-aided peptide design 111 6.3 Computational Design of Novel AMPs 112 6.4 Prediction Based on Biophysical Approaches 113 6.5 Concluding Remarks 113 Part iv: mechanisms of action: bioPhysics and structural biology 7 Antimicrobial Peptides: Multiple Mechanisms against a Variety of Targets 119 Li-av Segev-Zarko, Maria Luisa Mangoni and Yechiel Shai 7.1 Target Selectivity of Antimicrobial Peptides 120 7.2 Membrane-lytic Antimicrobial Peptides 121 7.3 Intracellular Targets of Antimicrobial Peptides 122 7.4 LPS and LTA Neutralization by Antimicrobial Peptides 122 7.5 Antibiofilm Antimicrobial Peptides 123 7.6 Antifungal Antimicrobial Peptides 124 7.7 Anticancer Antimicrobial Peptides 124 7.8 Antiviral Antimicrobial Peptides 125 7.9 Antimicrobial Peptide Modification and How It Affects the Mode of Action 126 7.9.1 Lipopeptides 126 7.9.2 Modification of amino acids content 126 7.10 Conclusion 127 8 Microbial Membranes and the Action of Antimicrobial Peptides 135 José Carlos Bozelli, Jr., Shirley Schreier and Richard M. Epand 8.1 Introduction 135 8.2 Physicochemical Properties of AMPs and the Molecular Organization of The Cell Envelope of Different Microorganisms 136 viii Contents 8.3 The Role of Cell Wall Components on AMP Toxicity 139 8.4 Membrane Lipid Composition and AMP Sensitivity 141 8.5 Antimicrobial Agents that Promote Clustering of Anionic Lipids 142 8.6 Synergistic Action of AMPs and Other Antimicrobial Agents 143 8.7 Summary and Future Perspective 143 9 Non-membranolytic Mechanisms of Action of Antimicrobial Peptides – Novel Therapeutic Opportunities? 149 Marco Scocchi, Mario Mardirossian, Giulia Runti and Monica Benincasa 9.1 Introduction 149 9.2 Intracellular Mode of Action 151 9.2.1 Inhibition of molecular chaperones and of protein synthesis 151 9.2.2 Binding to DNA and inhibition of transcription/replication 155 9.3 Cell Surface Modes of Action 156 9.3.1 Cell wall inhibition 156 9.3.2 Inhibition of cytokinesis 157 9.4 Other Membrane-independent Mechanisms of Bacterial Killing 158 9.5 Immune Modulatory Effects 158 9.6 Towards Novel Therapeutic Opportunities 159 9.7 Concluding Remarks 160 10 Structural Insight into the Mechanisms of Action of Antimicrobial Peptides and Structure-based Design 169 Guangshun Wang 10.1 Introduction to Structural Methods and Membrane Models 170 10.2 Three-dimensional Structures of Antimicrobial Peptides 171 10.2.1 α-helical AMPs 171 10.2.2 β-sheet AMPs 174 10.2.3 αβ-AMPs 176 10.2.4 Non-αβ AMPs 177 10.3 Structure-based Peptide Design 179 10.3.1 Structural basis for the improvement of peptide druggability 179 10.3.2 Stable scaffold-based grafting 180 10.4 Concluding Remarks 180 Part v: novel theraPeutic strategies: synergy, immune modulation, surface coating and delivery 11 Synergy of Antimicrobial Peptides 188 Mobaswar H. Chowdhury, Gill Diamond and Lisa Kathleen Ryan 11.1 Introduction 188 11.2 Principles of Synergy of Antimicrobial Peptides 189 11.3 How Antimicrobial Peptides Synergize to Kill Microorganisms 190 11.4 Synergism of Antimicrobial Peptides with Conventional Antibiotics 192 11.5 Synergy with AMP Analogues 196 11.6 Conclusion 196 12 Surface Immobilization of Antimicrobial Peptides to Prevent Biofilm Formation 202 Biswajit Mishra, Scott Reiling and Guangshun Wang 12.1 Introduction 202 12.2 Surface Coating Methods 203 Contents ix 12.2.1 Non-peptide microbicidal materials 203 12.2.2 Antibiotic immobilized surfaces 204 12.2.3 Antimicrobial peptide immobilization 204 12.3 Chemical and Physical Characterization of Peptide Coated Surfaces 208 12.4 Antimicrobial and Antibiofilm Activities of Peptide Coated Surfaces 209 12.5 Mechanism of Action of Immobilized Peptides 212 12.6 Biocompatibility 213 12.7 Conclusions and Future Outlook 213 13 Sustained Delivery of Cathelicidin Antimicrobial Peptide-inducing Compounds to Minimize Infection and Enhance Wound Healing 219 Jingwei Xie, Gitali Ganguli-Indra, Arup K. Indra and Adrian F. Gombart 13.1 Introduction 219 13.2 The Role of the CAMP Gene in Protection against Infection 220 13.3 LL-37 Modulates the Host Immune Response 221 13.3.1 Formyl peptide receptor 2 (FPR2) 221 13.3.2 Purinergic receptor P2X7 222 13.3.3 Toll-like receptors (TLRs) 222 13.3.4 Other transmembrane receptors 222 13.4 Function of Vitamin D Signalling in Normal Skin Homeostasis 223 13.5 The Role of Vitamin D and CAMP/LL-37 in Cutaneous Wound Healing 225 13.6 Induction of CAMP Gene Expression by Other Natural Compounds 226 13.7 Preventing Infections and Improving Wound Healing with Vitamin D 3 and Other Immune Boosting Compounds 226 13.8 Summary 229 14 Immunomodulatory Activities of Cationic Host Defence Peptides and Novel Therapeutic Strategies 238 Kelli C. Wuerth and Robert E.W. Hancock 14.1 Classical AMPs and HDPs 239 14.1.1 Defensins 239 14.1.2 Cathelicidins 239 14.1.3 Histatins and liver-expressed antimicrobial peptides (LEAPs) 241 14.1.4 Modified and synthetic HDPs 241 14.2 Hormones and Neuropeptides: The New HDPs 241 14.2.1 Natriuretic peptides 241 14.2.2 Secretin family 244 14.2.3 Calcitonin family 244 14.2.4 Somatostatin family 244 14.2.5 Pro-opiomelanocortin derivatives 245 14.3 Activities of HDPs 245 14.3.1 Anti-infective/immunomodulatory 245 14.3.2 Antibiofilm 247 14.3.3 Anticancer 247 14.3.4 Wound healing and angiogenesis 248 14.3.5 Cardiovascular disease and metabolism 248 14.3.6 Adjuvants 248 14.4 HDPs as Therapeutics: Peptides in Clinical Trials 249 14.4.1 Challenges 251 14.5 Conclusions 252 Index 261