Synthesis and Characterization of Peptide Macrocycles as Novel, Bimodal Proteasome Inhibitors

Synthesis and Characterization of Peptide Macrocycles as Novel, Bimodal Proteasome Inhibitors
Author: David Lawrence Wilson
Publisher:
Total Pages: 0
Release: 2015
Genre: Protease inhibitors
ISBN:

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.

Peptide Macrocycles

Peptide Macrocycles
Author: Matthew B. Coppock
Publisher: Humana
Total Pages: 0
Release: 2022-10-02
Genre: Technology & Engineering
ISBN: 9781071616918

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.

Structure-based Design and Synthesis of Bimodal Proteasome Inhibitors as Therapeutic Agents

Structure-based Design and Synthesis of Bimodal Proteasome Inhibitors as Therapeutic Agents
Author: Zack Michael Strater
Publisher:
Total Pages: 0
Release: 2014
Genre: Enzyme kinetics
ISBN:

The proteasome is a multicatalytic enzyme responsible for degrading damaged, misfolded, and uneeded intracellular proteins. Since many vital cellular pathways rely on the degradative function of the proteasome, its dysregulation is implicated in the pathology of several diseases, thus making it an attractive target for inhibition. Here we report two novel tetrapeptide aldehyde inhibitors based on the structure of natural product TMC-95A, a potent noncovalent inhibitor of the proteasome. Conversion of the carbonyl of the C-terminal residue to an aldehyde enabled these inhibitors to covalently bind to the catalytic Thr residue of the proteasome's active site. The P1 and P3 residues, which engage with the primary active site pockets, were varied to mimic TMC-95A and MG-132, a well known peptide aldehyde proteasome inhibitor. The combination of covalent and noncovalent mechanisms of binding to the active site allow these compounds to bimodally inhibit the proteasome. Additionally, the P2 and P4 residues of two of the inhibitors were cyclized via a biaryl ether moiety in order to mimic the synthetically inaccessible macrocycle found in TMC-95A. The compounds were then tested in vitro with 20S proteasome using fluorometric reversible kinetics. The two macrocyclic lead compounds were also compared to linear peptide aldehyde analogs that were prepared and tested in the same fashion to the macrocycles. The resulting inhibition constants were used to evaluate the effect of the macrocycle, the addition of the aldehyde functionality, and to compare the different amino acid sequences. The aldehyde was found to greatly increase potency compared to noncovalent inhibitors with a similar structure. The compounds with amino acid sequences similar to MG-132 were the most potent (Ki̳ = 33 nM, 76 nm) while the cyclic compounds were found to be slightly less potent than their linear analogues. These compounds were also tested with chymotrypsin, calpain, and cruzain to investigate their inhibitory specificity. The kinetic data demonstrated that the general structure of the inhibitors showed much greater affinity for the proteasome than for the other proteases tested.

Self-Assembled Nanostructures

Self-Assembled Nanostructures
Author: Jin Zhang
Publisher: Springer Science & Business Media
Total Pages: 327
Release: 2006-04-11
Genre: Science
ISBN: 0306479419

Nanostructures refer to materials that have relevant dimensions on the nanometer length scales and reside in the mesoscopic regime between isolated atoms and molecules in bulk matter. These materials have unique physical properties that are distinctly different from bulk materials. Self-Assembled Nanostructures provides systematic coverage of basic nanomaterials science including materials assembly and synthesis, characterization, and application. Suitable for both beginners and experts, it balances the chemistry aspects of nanomaterials with physical principles. It also highlights nanomaterial-based architectures including assembled or self-assembled systems. Filled with in-depth discussion of important applications of nano-architectures as well as potential applications ranging from physical to chemical and biological systems, Self-Assembled Nanostructures is the essential reference or text for scientists involved with nanostructures.

Protein Self-Assembly

Protein Self-Assembly
Author: Jennifer J. McManus
Publisher: Humana
Total Pages: 266
Release: 2020-08-08
Genre: Science
ISBN: 9781493996803

This volume explores experimental and computational approaches to measuring the most widely studied protein assemblies, including condensed liquid phases, aggregates, and crystals. The chapters in this book are organized into three parts: Part One looks at the techniques used to measure protein-protein interactions and equilibrium protein phases in dilute and concentrated protein solutions; Part Two describes methods to measure kinetics of aggregation and to characterize the assembled state; and Part Three details several different computational approaches that are currently used to help researchers understand protein self-assembly. 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. Thorough and cutting-edge, Protein Self-Assembly: Methods and Protocols is a valuable resource for researchers who are interested in learning more about this developing field.

Macromolecules

Macromolecules
Author: F Bovey
Publisher: Elsevier
Total Pages: 566
Release: 2012-12-02
Genre: Science
ISBN: 0323145795

Macromolecules is an introductory book about macromolecules, specifically about the fundamental aspects of macromolecules, such as their nature, the ways they are formed, and their behavior. This book also focuses on the basics of macromolecules, which includes history, composition, and properties. The topics covered in this book include polymerization kinetics, chemical reactions, and degradation of macromolecules. This book also discusses biological molecules, including naturally occurring materials, synthetic macromolecules, and model compounds. Students majoring in chemistry or other related fields, such as materials engineering, will find this book very useful.

Topology of Polymers

Topology of Polymers
Author: Koya Shimokawa
Publisher: Springer Nature
Total Pages: 81
Release: 2019-12-06
Genre: Mathematics
ISBN: 4431568883

Plastics, films, and synthetic fibers are among typical examples of polymer materials fabricated industrially in massive quantities as the basis of modern social life. By comparison, polymers from biological resources, including proteins, DNAs, and cotton fibers, are essential in various processes in living systems. Such polymers are molecular substances, constituted by the linking of hundreds to tens of thousands of small chemical unit (monomer) components. Thus, the form of polymer molecules is frequently expressed by line geometries, and their linear and non-linear forms are believed to constitute the fundamental basis for their properties and functions. In the field of polymer chemistry and polymer materials science, the choice of macromolecules has continuously been extended from linear or randomly branched forms toward a variety of precisely controlled topologies by the introduction of intriguing synthetic techniques. Moreover, during the first decade of this century, a number of impressive breakthroughs have been achieved to produce an important class of polymers having a variety of cyclic and multicyclic topologies. These developments now offer unique opportunities in polymer materials design to create unique properties and functions based on the form, i.e., topology, of polymer molecules. The introduction and application of topological geometry (soft geometry) to polymer molecules is a crucial requirement to account for the basic geometrical properties of polymer chains uniquely flexible in nature, in contrast to small chemical compounds conceived upon Euclidian geometry (hard geometry) principles. Topological geometry and graph theory are introduced for the systematic classification and notation of the non-linear constructions of polymer molecules, including not only branched but also single cyclic and multicyclic polymer topologies. On that basis, the geometrical–topological relationship between different polymers having distinctive constructions is discussed. A unique conception of topological isomerism is thus formed, which contrasts with that of conventional constitutional and stereoisomerism occurring in small chemical compounds. Through the close collaboration of topology experts Shimokawa and Ishihara and the polymer chemist Tezuka, this monograph covers the fundamentals and selected current topics of topology applied in polymers and topological polymer chemistry. In particular, the aim is to provide novel insights jointly revealed through a unique interaction between mathematics (topology) and polymer materials science.

Coumarin and Its Derivatives

Coumarin and Its Derivatives
Author: Maria João Matos
Publisher: Mdpi AG
Total Pages: 416
Release: 2021-12-29
Genre: Science
ISBN: 9783036527758

Coumarins are widely distributed in nature and can be found in a large number of naturally occurring and synthetic bioactive molecules. The unique and versatile oxygen-containing heterocyclic structure makes them a privileged scaffold in Medicinal Chemistry. Many coumarin derivatives have been extracted from natural sources, designed, synthetized, and evaluated on different pharmacological targets. In addition, coumarin-based ion receptors, fluorescent probes, and biological stains are growing quickly and have extensive applications to monitor timely enzyme activity, complex biological events, as well as accurate pharmacological and pharmacokinetic properties in living cells. The extraction, synthesis, and biological evaluation of coumarins have become extremely attractive and rapidly developing topics. A large number of research and review papers have compiled information on this important family of compounds in 2020. Research articles, reviews, communications, and concept papers focused on the multidisciplinary profile of coumarins, highlighting natural sources, most recent synthetic pathways, along with the main biological applications and theoretical studies, were the main focus of this book. The huge and growing range of applications of coumarins described in this book is a demonstration of the potential of this family of compounds in Organic Chemistry, Medicinal Chemistry, and different sciences related to the study of natural products. This book includes 23 articles: 17 original papers and six review papers.