CONTROL MECHANISMS IN DEVELOPMENTAL PROCESSES
CONTENTS PART I: NATURAL ANTIMICROBIAL PEPTIDES: NOMENCLATURE, CLASSIFICATION AND INTERESTING TEMPLATES FOR PEPTIDE ENGINEERING A DATABASE VIEW OF NATURALLY OCCURRING ANTIMICROBIAL PEPTIDES: NOMENCLATURE, CLASSI? CATION AND AMINO ACID SEQUENCE ANALYSIS 1 1 DATABASE SCOPE AND OVERVIEW 1 2 NOMENCLATURE OF ANTIMICROBIAL PEPTIDES 1 2 1 PEPTIDE-BASED METHOD 1 2 2 SOURCE-BASED METHOD 1 2 3 SOURCE AND PEPTIDE COMBINED METHOD 1 3 ANNOTATION AND CLASSI? CATION OF ANTIMICROBIAL PEPTIDES 1 3 1 SOURCE ORGANISMS AND PEPTIDE FAMILY CLASSI? CATION 1 3 2 CLASSI? CATION BASED ON BIOLOGICAL ACTIVITIES 1 3 3 CLASSI? CATION BASED ON PEPTIDE CHARACTERISTICS 1 3 4 PEPTIDE-BINDING TARGETS AND MECHANISMS OF ACTION 1 4 AMINO ACID SEQUENCE ANALYSIS OF ANTIMICROBIAL PEPTIDES 1 5 CONCLUDING REMARKS LANTIBIOTIC-RELATED RESEARCH AND THE APPLICATION THEREOF 2 1 INTRODUCTION TO BACTERIOCINS 2 2 BIOSYNTHESIS AND POST-TRANSLATIONAL MODI? CATIONS 2 3 CLASSI? CATION 2 4 LANTIBIOTIC SUBGROUPS: BIOLOGY, STRUCTURE AND MODE OF ACTION 2 4 1 NISIN-LIKE LANTIBIOTICS 2 4 2 EPIDERMIN-LIKE LANTIBIOTICS 2 4 3 PLANOSPORICIN- AND STREPTIN-LIKE LANTIBIOTICS 2 4 4 PEP5-LIKE PEPTIDES 2 4 5 LACTICIN 481-LIKE LANTIBIOTICS 2 4 6 MERSACIDIN-LIKE LANTIBIOTICS 2 4 7 LTNA2-LIKE PEPTIDES 2 4 8 OTHER TYPE II LANTIBIOTICS 2 5 CURRENT AND FUTURE USE OF LANTIBIOTICS FOR FOOD APPLICATIONS 2 6 LANTIBIOTICS AND THEIR MEDICAL APPLICATIONS 2 7 ENGINEERING OF LANTIBIOTICS 2 8 SCREENING FOR NEW LANTIBIOTICS 2 9 CONCLUDING REMARKS AND PERSPECTIVES ANTIMICROBIAL PEPTIDES IN PLANTS 3 1 INTRODUCTION TO PLANT ANTIMICROBIAL PEPTIDES 3 1 1 LIPID-TRANSFER PROTEINS 3 1 2 THIONINS 3 1 3 PLANT DEFENSINS 3 1 4 CHITIN-BINDING PEPTIDES 3 1 5 MISCELLANEOUS AMPS FROM PLANTS 3 1 6 NON-RIBOSOMAL ANTIMICROBIAL PEPTIDES 3 2 CYCLOTIDES 3 2 1 DIVERSITY OF PLANT CYCLOTIDES 3 2 2 DETECTION AND ISOLATION OF CYCLOTIDES 3 2 3 CYCLOTIDE BIOSYNTHESIS 3 2 4 BIOLOGICAL ACTIVITIES OF CYCLOTIDES 3 2 5 CYCLOTIDE ENGINEERING AND MASS PRODUCTION 3 3 CONCLUDING REMARKS AND PERSPECTIVES PART II: EXPANDING THE PEPTIDE SPACE: PREDICTION METHODS, DESIGN STRATEGIES AND PEPTIDOMIMETICS DATABASE-AIDED PREDICTION AND DESIGN OF NOVEL ANTIMICROBIAL PEPTIDES 4 1 DATABASE-AIDED ANTIMICROBIAL PEPTIDE PREDICTION 4 1 1 PREDICTION BASED ON MATURE PEPTIDES 4 1 2 PREDICTION BASED ON HIGHLY CONSERVED PROPEPTIDE SEQUENCES 4 1 3 PREDICTION BASED ON BOTH PROPEPTIDES AND MATURE PEPTIDES 4 1 4 PREDICTION BASED ON PROCESSING ENZYMES 4 1 5 GENOMIC CONTEXT-BASED BACTERIOCIN PREDICTION 4 2 DATABASE-AIDED PEPTIDE DESIGN AND IMPROVEMENT 4 2 1 DATABASE SCREENING FOR HIV INHIBITORY ANTIMICROBIAL PEPTIDES 4 2 2 SEQUENCE SHU? ING IS A PRIMITIVE COMBINATORIAL APPROACH 4 2 3 THE HYBRID APPROACH AND GRAMMAR-BASED PEPTIDE DESIGN 4 2 4 DE NOVO PEPTIDE DESIGN 4 2 5 DATABASE-AIDED ENHANCEMENT OF PEPTIDE ANTI-HIV ACTIVITY 4 3 STRATEGIES FOR IMPROVING CELL SELECTIVITY OF AMPS 4 4 STRATEGIES FOR IMPROVING PEPTIDE STABILITY TO PROTEASES 4 5 CONCLUDING REMARKS DISCOVERY OF NOVEL ANTIMICROBIAL PEPTIDES USING COMBINATORIAL CHEMISTRY AND HIGH-THROUGHPUT SCREENING 5 1 THE INTERFACIAL ACTIVITY MODEL OF AMP ACTIVITY 5 2 COMBINATORIAL CHEMISTRY METHODS 5 2 1 OVERVIEW OF LIBRARY SYNTHESIS 5 2 2 NON-INDEXED METHODS 5 2 3 INDEXED METHODS 5 3 HIGH-THROUGHPUT SCREENING 5 3 1 BIOLOGICAL ASSAYS 5 3 2 SELECTION OF BROAD-SPECTRUM PEPTIDE ANTIBIOTICS 5 3 3 NON-BIOLOGICAL ASSAYS 5 4 ACCOMPLISHMENTS 5 4 1 BEYOND HIGH-THROUGHPUT SCREENING 5 5 FUTURE DIRECTIONS CHEMICAL MIMICS WITH SYSTEMIC E? CACY 6 1 INTRODUCTION 6 2 DE NOVO-DESIGNED RIGID PEPTIDOMIMETICS 6 2 1 HAIRPIN-SHAPED PEPTIDES 6 2 2 PEPTOIDS 6 2 3 ARYLAMIDES 6 3 ACYL-LYSYL OLIGOMERS 6 3 1 DESIGN 6 3 2 STRUCTURE–ACTIVITY RELATIONSHIPS 6 3 3 ANTIBACTERIAL PROPERTIES 6 3 4 ANTIPARASITAL PROPERTIES 6 4 CONCLUDING REMARKS AND PERSPECTIVES PART III: BIOPHYSICS, STRUCTURAL BIOLOGY AND MECHANISM OF ACTION OF ANTIMICROBIAL PEPTIDES BIOPHYSICAL ANALYSIS OF MEMBRANE-TARGETING ANTIMICROBIAL PEPTIDES: MEMBRANE PROPERTIES AND THE DESIGN OF PEPTIDES SPECI? CALLY TARGETING GRAM-NEGATIVE BACTERIA 7 1 DI? ERENCES IN CHEMICAL COMPOSITION AND MOLECULAR ORGANIZATION OF GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA 7 2 ROLE OF BACTERIAL MEMBRANE LIPID COMPOSITION IN ANTIMICROBIAL SENSITIVITY 7 3 ANTIMICROBIAL AGENTS THAT TARGET THE OUTER MEMBRANE OF GRAM-NEGATIVE BACTERIA 7 4 ANTIMICROBIAL AGENTS THAT PROMOTE CLUSTERING OF ANIONIC LIPIDS 7 4 1 EVIDENCE FOR LIPID CLUSTERING 7 4 2 BACTERIAL SPECIES SPECI? CITY OF TOXICITY 7 4 3 PUTATIVE MECHANISM OF ACTION 7 4 4 PROPERTIES OF ANTIMICROBIAL AGENTS THAT FAVOUR CLUSTERING 7 4 5 SOURCES OF ENERGY TO ACCOUNT FOR CLUSTERING AND ENTROPY OF DEMIXING 7 5 CONCLUDING REMARKS AND PERSPECTIVES NON-MEMBRANE TARGETS OF ANTIMICROBIAL PEPTIDES: NOVEL THERAPEUTIC OPPORTUNITIES? 8 1 INTRODUCTION 8 2 BUFORIN II: ?-HELICAL AMP WITH SINGLE PROLINE RESIDUE BINDING TO NUCLEIC ACIDS 8 3 PR-39 AND INDOLICIDIN: MAMMALIAN PROLINE-RICH PEPTIDES INHIBITING MACROMOLECULE SYNTHESIS AND CELL DIVISION 8 4 APIDAECIN, DROSOCIN AND PYRRHOCORICIN: SHORT, INSECT PROLINE-RICH PEPTIDES BINDING TO HEAT-SHOCK PROTEIN DNAK 8 5 CONCLUDING REMARKS AND PERSPECTIVES STRUCTURAL STUDIES OF ANTIMICROBIAL PEPTIDES PROVIDE INSIGHT INTO THEIR MECHANISMS OF ACTION 9 1 HUMAN DEFENSINS AND CATHELICIDINS 9 2 BACTERIAL EXPRESSION AND PURI? CATION OF ANTIMICROBIAL PEPTIDES 9 3 STRUCTURAL STUDIES OF MEMBRANE-TARGETING ANTIMICROBIAL PEPTIDES 9 3 1 MEMBRANE-MIMETIC MODELS 9 3 2 NMR METHODS 9 3 3 THREE-DIMENSIONAL STRUCTURES OF ANTIMICROBIAL PEPTIDES 9 3 4 INTERACTIONS OF ANTIMICROBIAL PEPTIDES WITH BACTERIAL MEMBRANES BY NMR SPECTROSCOPY 9 3 5 STRUCTURAL BASIS OF PEPTIDE SELECTIVITY 9 4 STRUCTURE-BASED PEPTIDE ENGINEERING 9 5 CONCLUDING REMARKS AND PERSPECTIVES PART IV: NOVEL THERAPEUTIC STRATEGIES TO BOLSTER HOST DEFENCE 10 LUNG INFECTION: SHIFT ING THE EQUILIBRIUM TOWARDS THE FREE AND ACTIVE FORM OF HUMAN LL-37 AND THE DESIGN OF ALTERNATIVE ANTIMICROBIAL AGENTS 10 1 INTRODUCTION 10 1 2 INTERACTION OF POLYVALENT CATIONS WITH LINEAR POLYELECTROLYTES 10 2 PRODUCTION OF ANIONIC POLYELECTROLYTES BY HOST AND MICROBIAL SOURCES 10 3 SEQUESTRATION AND INACTIVATION OF LL-37 BY DNA AND F-ACTIN 10 4 RELEASING LL-37 FROM POLYELECTROLYTE BUNDLES 10 4 1 SEVERING POLYMERS WITH DNASE, GELSOLIN AND ALGINASE 10 4 2 DESTABILIZING BUNDLES WITH SMALL MULTIVALENT ANIONS 10 5 DESIGNING ANTIMICROBIAL AGENTS RESISTANT TO INACTIVATION BY POLYELECTROLYTES 10 5 1 CATIONIC STEROIDS: MINIMIZING AND REDISTRIBUTING CHARGE 10 5 2 INCREASING THE HYDROPHOBICITY OF ANTIMICROBIAL AGENTS 10 6 POSSIBLE THERAPEUTIC USE 10 6 1 SELECTIVE USE IN SOME BODY ? UIDS AND NOT OTHERS 10 6 2 STIMULATION OF HOST CELLS 10 7 CONCLUSION 11 ROLE OF VITAMIN D IN THE ENHANCEMENT OF ANTIMICROBIAL PEPTIDE GENE EXPRESSION 11 1 VITAMIN D 11 2 EARLY HISTORY OF VITAMIN D 11 3 VITAMIN D DE? CIENCY 11 4 VITAMIN D SIGNALLING AND MECHANISMS OF ACTION 11 5 OVERVIEW OF VITAMIN D AND IMMUNE SYSTEM REGULATION 11 6 VITAMIN D AS A REGULATOR OF ANTIMICROBIAL PEPTIDE GENE EXPRESSION 11 7 ANTIMICROBIAL PEPTIDES 11 8 REGULATION OF DEFB2/HBD-2 EXPRESSION BY 1,25D 11 9 1,25D REGULATION OF LL-37 IS HUMAN AND PRIMATE SPECI? C 11 10 BROADER PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL IMPLICATIONS OF THE REGULATION OF LL-37 EXPRESSION BY 1,25D 11 11 THERAPEUTIC ROLE FOR VITAMIN D ANALOGUES 12 FINE TUNING HOST RESPONSES IN THE FACE OF INFECTION: EMERGING ROLES AND CLINICAL APPLICATIONS OF HOST DEFENCE PEPTIDES 12 1 MAMMALIAN HOST DEFENCE (ANTIMICROBIAL) PEPTIDES 12 1 1 DEFENSINS 12 1 2 CATHELICIDINS 12 2 THE ROLE OF ENDOGENOUS HOST DEFENCE PEPTIDES IN THE RESPONSE TO INFECTION 12 2 1 NATRIURETIC PEPTIDES 12 3 POTENTIAL THERAPEUTIC USES BEYOND ANTI-INFECTIVE ACTIVITY 12 3 1 ADJUVANT POTENTIAL 12 3 2 WOUND-HEALING ACTIVITY 12 4 RECENT CLINICAL ADVANCES IN THERAPEUTIC APPLICATION OF HOST DEFENCE PEPTIDES 12 5 INNATE DEFENCE REGULATORS AS ANTI-INFECTIVE THERAPEUTICS 12 6 RATIONAL DESIGN OF IMMUNOMODULATORY PEPTIDES 12 7 LIMITATIONS AND CHALLENGES 12 8 CONCLUSIONS