Note: Cover -- Cyclic Peptides: From Bioorganic Synthesis to Applications -- Contents -- Chapter 1 - An Introduction to Cyclic Peptides -- 1.1 Of Peptides and Proteins (and Small Molecules) -- 1.2 Conformational Constraints -- 1.3 Cyclic Peptides as Pharmaceutical Agents -- 1.4 End of the Prologue -- References -- Chapter 2 - The Biosynthesis of Cyclic Peptides - RiPPs - An Overview -- 2.1 Introduction -- 2.2 Cyanobactin Biosynthesis -- 2.3 Lanthipeptides -- 2.4 Thiopeptides -- 2.5 Bottromycin -- 2.6 Cyclic RiPPs from Plants: Cyclotides and Orbitides -- 2.7 Cyclic RiPPs from Mushrooms: Amanitins and Dikaritins -- 2.8 Conclusion and Outlook -- References -- Chapter 3 - Thioesterase Domain-mediated Macrocyclization of Non-ribosomal Peptides -- 3.1 Introduction -- 3.2 Types of Macrocyclic Non-ribosomal Peptide -- 3.2.1 Cyclic Peptides -- 3.2.2 Cyclic Depsipeptides -- 3.2.3 Cyclic Thiodepsipeptides -- 3.2.4 Cyclic Imino Peptides -- 3.3 Biosynthesis of Macrocyclic NRPs -- 3.3.1 NRP Biosynthesis -- 3.3.2 Thioesterase Domains -- 3.3.2.1 Type I TE Domains -- 3.3.2.2 Type II TE Domains -- 3.3.3 Other Termination Domains -- 3.3.3.1 Reductase Domains -- 3.3.3.2 Condensation(-like) Domains -- 3.4 Mechanistic Insights into TE Domain-catalyzed Peptide Cyclization and Release -- 3.4.1 Loading Step -- 3.4.2 Releasing Step -- 3.5 The Application of TE-I Domains for Synthesis of Cyclic Peptide Analogues -- 3.5.1 Excised TE-I Domains -- 3.5.2 Chemoenzymatic Approaches to Generate Natural Product Analogues -- 3.6 Insight into the Interaction Between the TE-I and PCP Domains -- 3.6.1 Interaction with the apo-PCP Domain -- 3.6.2 Interaction with the holo-PCP Domain -- 3.7 Summary and Outlook -- Acknowledgements -- References -- Chapter 4 - The Biosynthetic Machinery and Its Potential to Deliver Unnatural Cyclic Peptides. , 4.1 Non-natural Cyclic RiPPs - Expanding the Structural Space and Activities -- 4.1.1 The Supplementation-based Incorporation Approach -- 4.1.2 Genetic Code Expansion -- 4.2 Cyclic NRPs with New-to-nature Modifications -- 4.2.1 Precursor-directed Biosynthesis -- 4.2.2 Mutasynthesis -- 4.2.3 Combinatorial Biosynthesis and Domain Engineering -- Acknowledgements -- References -- Chapter 5 - Modulation of Protein-Protein Interactions Using Cyclic Peptides -- 5.1 Introduction -- 5.2 Structure-based Design -- 5.2.1 "Classic" Cyclic Peptides -- 5.2.2 Secondary Structure Mimetics -- 5.2.2.1 Cyclic Peptide Turns -- 5.2.2.2 Cyclic Peptide β-strands -- 5.2.2.3 Cyclic Helical Peptides -- 5.3 In silico Approaches -- 5.4 Fragment Screening and Combinatorial Approaches -- 5.5 In vitro Methods -- 5.5.1 Cellular Approaches -- 5.5.1.1 Phage Display -- 5.5.1.2 Yeast and Bacterial Display -- 5.5.2 Non-cellular Approaches -- 5.5.2.1 Ribosome Display and mRNA Display -- 5.5.2.2 CIS Display -- 5.6 Final Remarks -- Acknowledgements -- References -- Chapter 6 - Biology and Synthesis of the Argyrins -- 6.1 Introduction -- 6.2 Biological Activity -- 6.3 Synthesis -- 6.3.1 Biosynthesis -- 6.3.2 Ley's Total Synthesis -- 6.3.3 Kalesse's Total Synthesis -- 6.3.4 Jiang's Total Syntheses -- 6.3.5 Chan's Approach to Argyrin Analogues -- References -- Chapter 7 - Peptide Cross-links Catalyzed by Metalloenzymes in Natural Product Biosynthesis -- 7.1 Introduction -- 7.2 Penicillin Antibiotics -- 7.2.1 Penicillin Biosynthesis -- 7.2.2 Isopenicillin N Synthase -- 7.2.3 IPNS Mechanism -- 7.2.4 Impact of Penicillin and Its Biosynthesis -- 7.3 Glycopeptide Antibiotics -- 7.3.1 Oxy Enzymes in Glycopeptide Biosynthesis -- 7.3.2 Structural Characterization of Oxy Enzymes -- 7.3.3 Mechanistic Proposals for Oxy Enzymes -- 7.4 Radical SAM Enzymes Involved in Intramolecular RiPP Cross-links. , 7.4.1 PQQ -- 7.4.2 Sactipeptides -- 7.4.3 Streptide -- 7.4.4 Mechanisms of RiPP Cyclizations by Radical SAM Enzymes -- 7.5 Conclusions -- Acknowledgements -- References -- Chapter 8 - Double-click Stapled Peptides for Inhibiting Protein-Protein Interactions -- 8.1 Introduction -- 8.2 Non-proteogenic Amino Acid Synthesis -- 8.3 Peptide Sequence Optimization and Use of Functionalized Staple Linkages for Modulating the Cellular Activity of Stapled Pepti... -- 8.4 Metal-free Strain-promoted Peptide Stapling -- 8.5 Constrained Macrocyclic Non-α-helical Peptide Inhibitors -- 8.5.1 Design of Macrocyclic Peptide Inhibitors to Target the Substrate-recognition Domain of Tankyrase and Antagonize Wnt Signali... -- 8.5.2 Development of Cell-permeable, Non-helical, Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Can... -- Acknowledgements -- References -- Chapter 9 - Libraries of Head-to-tail Peptides -- 9.1 Introduction -- 9.2 Chemically Synthesized Libraries -- 9.2.1 Synthesis and Deconvolution of Diverse Linear Peptide Libraries -- 9.2.2 Head-to-tail Cyclization of Peptide Libraries -- 9.2.3 Deconvolution Strategies for Head-to-tail Cyclic Peptide Libraries -- 9.3 Genetically Derived Libraries -- 9.3.1 SICLOPPS -- 9.3.2 Genetically Encoded Cyclic Peptide Library Production In vitro -- 9.4 Conclusion -- References -- Chapter 10 - An Introduction to Bacterial Lasso Peptides -- 10.1 An Introduction to Bacterial Lasso Peptides -- 10.2 Investigation of Lasso Peptide Structures -- 10.3 Biological Functions of Lasso Peptides -- 10.4 Lasso Peptides as Scaffolds for Drug Development -- References -- Chapter 11 - Biological Synthesis and Affinity-based Selection of Small Macrocyclic Peptide Ligands -- 11.1 Introduction -- 11.2 Selection of Cyclic Peptides from Libraries Composed of Canonical Amino Acids. , 11.2.1 Head-to-tail Peptide Cyclization Using Split-inteins (SICLOPPS) -- 11.2.2 Phage/Phagemid Display -- 11.2.3 mRNA Display, cDNA Display and Ribosome Display -- 11.3 Broadening Library Chemical Diversity -- 11.3.1 Genetic Code Expansion -- 11.3.2 Genetic Code Reprogramming in Reconstituted Translation Systems -- 11.3.3 Enzymatic Aminoacylation by Natural AARSs -- 11.3.4 Aminoacylation of tRNAs Catalyzed by Flexizymes -- 11.3.5 Further Developments -- 11.4 Genetically Engineered Selections of Target-binding Macrocyclic Peptides -- 11.4.1 Selections Involving Genetic Code Expansion -- 11.4.2 Selections Involving ARS-mediated Genetic Code Reprogramming -- 11.4.3 Selections Involving FIT-mediated Genetic Code Reprogramming -- 11.5 Summary -- Acknowledgements -- References -- Chapter 12 - Mass Spectrometric Analysis of Cyclic Peptides -- 12.1 Classification of Cyclic Peptides -- 12.2 Nomenclature -- 12.3 Strategies for Structural Analysis -- 12.4 Ionization Methods -- 12.5 Fragmentation Methods -- 12.5.1 Threshold Dissociations -- 12.5.2 Ion-Electron Dissociations (ExD) -- 12.5.3 MALDI-related Methods -- 12.6 Application of Tandem Mass Spectrometry to Cyclic Peptides -- 12.6.1 General Procedure -- 12.6.2 Metal Complexation -- 12.6.3 Ion-Electron Dissociation (ExD) for Cyclic Peptides -- 12.6.4 Post-source Decay and In-source Decay -- 12.6.5 Ion Mobility-mass Spectrometry of Cyclic Peptides -- 12.6.6 Quantification -- 12.7 Conclusions -- References -- Chapter 13 - Experimental and Computational Approaches to the Study of Macrocycle Conformations in Solution -- 13.1 Introduction -- 13.2 Overview of Conformation Elucidation Techniques -- 13.2.1 X-ray Crystallography -- 13.2.2 Purely Computational Methods -- 13.2.3 Hybrid Methods -- 13.3 NMR Assignment and General Considerations -- 13.3.1 Introduction -- 13.3.2 General Consideration: Solvent Systems. , 13.3.3 Determining 2D Structure: Primary Sequence -- 13.4 Conformational Information from NMR -- 13.4.1 Introduction -- 13.4.2 3J Correlations -- 13.4.3 Through-space Couplings -- 13.4.4 Establishing Cis-Trans Relationships for 3° Amides -- 13.4.5 Residual Dipolar Couplings (RDCs) -- 13.4.6 Measures of Intramolecular Hydrogen Bonding -- 13.4.6.1 Temperature Shift Analysis -- 13.4.6.2 H-D Exchange -- 13.5 Generation of NMR-informed Solution Conformations -- 13.5.1 Unrestrained Conformation Generation and Sampling -- 13.5.1.1 Sampling -- 13.5.1.2 Energetic Comparisons -- 13.5.2 Naïve Sampling and NMR-best Fit Selection -- 13.5.2.1 Single Conformer Fitting -- 13.5.2.2 Fitting NMR Data to Conformational Ensembles -- 13.5.2.3 NMR Chemical Shift-based Methods -- References -- Chapter 14 - Trends in Cyclotide Research -- 14.1 Introduction -- 14.2 Trends in the Growth of the Cyclotide Field -- 14.3 Categories of Cyclotide Research: an Analysis -- 14.3.1 Peptide-based Discovery -- 14.3.2 Gene-based Discovery and Cyclotide Gene Regulation -- 14.3.3 Analysis -- 14.3.4 Structures, Folding and Dynamics -- 14.3.5 Bioactivity -- 14.3.6 Biosynthesis -- 14.3.7 Synthesis -- 14.3.8 Drug Design and Protein Engineering Applications -- 14.3.9 Membrane Binding, Cell Penetration and Toxicity -- 14.4 Reviews -- 14.5 Conclusions -- Acknowledgements -- References -- Chapter 15 - Cyclic Peptides - A Look to the Future -- 15.1 Introduction -- 15.1.1 Advantages of Cyclic Peptides -- 15.2 Synthetic and Biosynthetic Approaches to Cyclic Peptides -- 15.2.1 Synthetic Methods for Cyclization -- 15.2.2 Biochemical Methods for Cyclization -- 15.3 PK/ADMET Properties of Cyclic Peptides -- 15.3.1 Introduction -- 15.3.2 Prediction of PK/ADMET Properties of Cyclic Peptides: The New 'Beyond Rule of 5' Guidelines -- 15.3.3 Backbone Modifications Affecting PK and ADMET. , 15.4 Prediction of Structures of Cyclic Peptides.