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This volume explores the latest techniques and strategies used to study the field of peptide macrocycles. The chapters in this book ae organized into four parts: macrocycles synthesis, combinational library synthesis and screening, macrocycle characterization, and unique applications. Part One looks at a variety of peptide cyclization methodologies, and Part Two describes methods for the creation of peptide macrocycles libraries and their subsequent screening against biological targets of interest. Part Three discusses the study and characterization of peptide macrocycle-target interactions, and Part Four introduces unique applications for peptide macrocycles, from higher-order structure formation to post-synthetic functional modifications. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and comprehensive, Peptide Macrocycles: Methods and Protocols is a valuable resource for both novice and expert researchers looking to learn more about this developing field.
This volume explores the latest techniques and strategies used to study the field of peptide macrocycles. The chapters in this book ae organized into four parts: macrocycles synthesis, combinational library synthesis and screening, macrocycle characterization, and unique applications. Part One looks at a variety of peptide cyclization methodologies, and Part Two describes methods for the creation of peptide macrocycles libraries and their subsequent screening against biological targets of interest. Part Three discusses the study and characterization of peptide macrocycle-target interactions, and Part Four introduces unique applications for peptide macrocycles, from higher-order structure formation to post-synthetic functional modifications. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and comprehensive, Peptide Macrocycles: Methods and Protocols is a valuable resource for both novice and expert researchers looking to learn more about this developing field.
Including case studies of macrocyclic marketed drugs and macrocycles in drug development, this book helps medicinal chemists deal with the synthetic and conceptual challenges of macrocycles in drug discovery efforts. Provides needed background to build a program in macrocycle drug discovery –design criteria, macrocycle profiles, applications, and limitations Features chapters contributed from leading international figures involved in macrocyclic drug discovery efforts Covers design criteria, typical profile of current macrocycles, applications, and limitations
This series provides a comprehensive resource for postgraduate students and for scientists in academia or industry wanting to learn topics outside their own areas of expertise.
Protein-protein interactions (PPI) are at the heart of the majority of cellular processes, and are frequently dysregulated or usurped in disease. Given this central role, the inhibition of PPIs has been of significant interest as a means of treating a wide variety of diseases. However, there are inherent challenges in developing molecules capable of disrupting the relatively featureless and large interfacial areas involved. Despite this, there have been a number of successes in this field in recent years using both traditional drug discovery approaches and innovative, interdisciplinary strategies using novel chemical scaffolds. This book comprehensively covers the various aspects of PPI inhibition, encompassing small molecules, peptidomimetics, cyclic peptides, stapled peptides and macrocycles. Illustrated throughout with successful case studies, this book provides a holistic, cutting-edge view of the subject area and is ideal for chemical biologists and medicinal chemists interested in developing PPI inhibitors.
The proteasome is a large, multicatalytic protease found in all forms of life. The proteasome is instrumental in the regulation of many cellular pathways such as cell cycle arrest and cell proliferation. For this reason, proteasome inhibitors are of interest in drug development because of their ability to regulate the asynchronous cell cycles of cancers. In particular, multiple myeloma has been shown to be receptive to treatment with proteasome inhibitors. In this study, two novel macrocyclic peptidyl aldehyde proteasome inhibitors 11 and 12 are reported. The design of 11 and 12 was bioinspired by the natural product TMC-95A, a macrocyclic tripeptide shown to potently and selectively inhibit the proteasome. Compounds 11 and 12 were designed to test the effects of the peptide macrocycle on inhibitory strength and specificity. Both inhibitors were identical in sequence, however 12 incorporated a biaryl ether linkage to mimic the macrocyclic structure of TMC-95. Additionally, both inhibitors incorporated a C-terminal aldehyde designed to covalently bind the proteasome's catalytic threonine residue and hydrophobic side chains to target the chymotrypsin-like activity of the proteasome. In vitro testing of both inhibitors revealed them to be potent and specific inhibitors of the chymotrypsin-like activity of the proteasome (11, Ki = 33 nM, 12, Ki = 76 nM). It was found that there was no trend to suggest that the peptide macrocycle conferred increased specificity or binding. Ex vivo assays for 12 showed it to be metabolically stable, readily taken up by HeLa cells, and perform on par with the well characterized proteasome inhibitor MG-132. Finally, QM/MM studies suggested that the oxindole moiety found in the macrocycle of TMC-95A is essential for specificity for the chymotrypsin-like active site of the proteasome.
A peptidomimetic is a small protein-like chain designed to mimic a peptide with adjusted molecular properties such as enhanced stability or biological activity. It is a very powerful approach for the generation of small-molecule-based drugs as enzyme inhibitors or receptor ligands. Peptidomimetics in Organic and Medicinal Chemistry outlines the concepts and synthetic strategies underlying the building of bioactive compounds of a peptidomimetic nature. Topics covered include the chemistry of unnatural amino acids, peptide- and scaffold-based peptidomimetics, amino acid-side chain isosteres, backbone isosteres, dipeptide isosteres, beta-turn peptidomimetics, proline-mimetics as turn inducers, cyclic scaffolds, amino acid surrogates, and scaffolds for combinatorial chemistry of peptidomimetics. Case studies in the hit-to-lead process, such as the development of integrin ligands and thrombin inhibitors, illustrate the successful application of peptidomimetics in drug discovery.
Building on the pioneering work in supramolecular chemistry from the last 20 years or so, this monograph addresses new and recent approaches to anion coordination chemistry. Synthesis of receptors, biological receptors and metallareceptors, the energetics of anion binding, molecular structures of anion complexes, sensing devices are presented and computational studies addressed to aid with the understanding of the different driving forces responsible for anion complexation. The reader is promised an actual picture of the state of the art for this exciting and constantly evolving field of supramolecular anion coordination chemistry. The topics range from ion channels to selective sensors, making it attractive to all researchers and PhD students with an interest in supramolecular chemistry.
Peptidomimetic macrocycles are valuable research tools and serve as lead compounds in drug discovery. We have developed two synthetic methods to access distinct isomeric macrocycles from a given peptide sequence; internal palladium(0)-catalyzed allylation, and large-ring forming Friedel-Crafts alkylation. These methods utilize a lipophilic template designed to impart favorable drug-like properties to the composite macrocycles relative to their linear peptide precursors. Structurally diverse macrocyclic peptidomimetics derived from these methods have the potential to identify small molecules effective against challenging targets involved in exposed protein surfaces.