Download or read book Synthetic Combinatorial Peptide Libraries and Their Application in Decoding Biological Interactions written by Michael Cameron Sweeney and published by . This book was released on 2005 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: The synthesis of peptides was revolutionized by the adoption of solid-phase synthetic techniques. Subsequent improvement, evolution, and refinement of this chemical technique has allowed research into areas of biology not previously accessible with such speed and breadth. Because of the efficiency and flexibility of the chemistry involved in peptide synthesis, libraries representing millions of unique natural, modified, or unnatural peptides can be constructed rapidly and in high enough purity as to obviate the need for purification. In this work, libraries were synthesized for screening against individual protein domains in an effort to both determine the preferred peptidyl binding partner types for each, as well as to establish an optimized, broadly applicable methodology for screening other domains. One of the problems encountered during the development of the screening methodology was the low success-rate of sequence determination for the peptides selected by each domain. Herein we report the successful modification of the peptide ladder mass spectrometry sequencing technique referred to as partial Edman degradation (PED). Success-rates were improved to greater than 90% for full-length sequencing determination of peptide up to 8-mers, even for more difficult phosphotyrosine (pY)-containing peptides. As a result of this improvement, three pY-binding Src Homology 2 (SH2) domains and two N-terminus binding Baculoviral Inhibitor-of-Apoptosis Repeat (BIR) domains were screened against their respective libraries and the preferred ligand types for each was determined. The advantage of sequencing by the PED method became especially clear in the case of the N-terminal SH2 (N-SH2) domain of Src Homology 2 Protien Tyrosine Phosphatase 2 (SHP-2) as previously unidentified sub-classes of binding consensus motifs were distinguishable due to the discreet nature of the sequencing technique. This work demonstrates the usefulness and potential generality of peptide library screening by this method.
Download or read book Combinatorial Peptide Library Protocols written by Shmuel Cabilly and published by Springer Science & Business Media. This book was released on 2008-02-02 with total page 320 pages. Available in PDF, EPUB and Kindle. Book excerpt: During the course of evolution, an imbalance was created between the rate of vertebrate genetic adaptation and that of the lower forms of living organisms, such as bacteria and viruses. This imbalance has given the latter the advantage of generating, relatively quickly, molecules with unexpected structures and features that carry a threat to vertebrates. To compensate for their weakness, vertebrates have accelerated their own evolutionary processes, not at the level of whole organism, but in specialized cells containing the genes that code for antibody molecules or for T-cell receptors. That is, when an immediate requirement for molecules capable of specific interactions arose, nature has preferred to speed up the mode of Darwinian evolution in pref- ence to any other approach (such as the use of X-ray diffraction studies and computergraphic analysis). Recently, Darwinian rules have been adapted for test tube research, and the concept of selecting molecules having particular characteristics from r- dom pools has been realized in the form of various chemical and biological combinatorial libraries. While working with these libraries, we noticed the interesting fact that when combinatorial libraries of oligopeptides were allowed to interact with different selector proteins, only the actual binding sites of these proteins showed binding properties, whereas the rest of the p- tein surface seemed "inert. " This seemingly common feature of protein- having no extra potential binding sites--was probably selected during evolution in order to minimize nonspecific interactions with the surrounding milieu.
Download or read book Combinatorial Libraries written by Riccardo Cortese and published by Walter de Gruyter. This book was released on 2013-08-26 with total page 248 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Combinatorial Library written by Lisa B. English and published by Springer Science & Business Media. This book was released on 2008-02-04 with total page 380 pages. Available in PDF, EPUB and Kindle. Book excerpt: The continued successes of large- and small-scale genome sequencing projects are increasing the number of genomic targets available for drug d- covery at an exponential rate. In addition, a better understanding of molecular mechanisms—such as apoptosis, signal transduction, telomere control of ch- mosomes, cytoskeletal development, modulation of stress-related proteins, and cell surface display of antigens by the major histocompatibility complex m- ecules—has improved the probability of identifying the most promising genomic targets to counteract disease. As a result, developing and optimizing lead candidates for these targets and rapidly moving them into clinical trials is now a critical juncture in pharmaceutical research. Recent advances in com- natorial library synthesis, purification, and analysis techniques are not only increasing the numbers of compounds that can be tested against each specific genomic target, but are also speeding and improving the overall processes of lead discovery and optimization. There are two main approaches to combinatorial library production: p- allel chemical synthesis and split-and-mix chemical synthesis. These approaches can utilize solid- or solution-based synthetic methods, alone or in combination, although the majority of combinatorial library synthesis is still done on solid support. In a parallel synthesis, all the products are assembled separately in their own reaction vessels or microtiter plates. The array of rows and columns enables researchers to organize the building blocks to be c- bined, and provides an easy way to identify compounds in a particular well.
Download or read book Combinatorial Peptide and Nonpeptide Libraries written by Günther Jung and published by John Wiley & Sons. This book was released on 2008-09-26 with total page 571 pages. Available in PDF, EPUB and Kindle. Book excerpt: With combinatorial chemistry millions of organic compounds can be produced simultaneously, quickly, and in most cases by automated procedures. These compound libraries are a cost-effective resource for the pharmaceutical industry in their search for biologically active lead structures. Furthermore simultaneous parallel synthesis of single peptides and peptide libraries solve the problem of the worldwide increasing demand for peptides. The synthetic methods described here in detail contribute to a forward-looking technology that has a high impact for industrial and academic research. Fast and efficient analytical techniques are essential for using the complicated product mixtures and detecting by-products. Various synthetic approaches and technologies, mass spectrometry, and screening assays are discussed extensively. This book is a must and an indispensible source of information for every researcher in this rapidly developing field, which spans organic synthesis, biochemistry, biotechnology, pharmaceutical, medicinal, and clinical chemistry.
Download or read book Development of New Approaches for the Synthesis and Decoding of One bead One compound Cyclic Peptide Libraries written by Xinxia Liang and published by . This book was released on 2016 with total page 173 pages. Available in PDF, EPUB and Kindle. Book excerpt: A great number of cellular and biological processes depend, at some level, on protein-protein interactions (PPI). Their manipulation with chemical compounds has provided a great potential for the discovery of new drugs. Despite the increasing demand for molecules able to interrupt specific PPI, the development of small PPI inhibitors is beset by a number of challenges such as the large size of the interaction interface. Based on the interface's nature, the ability to mimic protein secondary structures is very important to bind a protein and inhibit PPI. With their interesting peptidomimetic abilities and pharmacological properties, cyclic peptides are very promising templates to discover protein ligands and development new PPI inhibitors. To fully exploit the great diversity accessible with cyclic peptides, the one-bead-one-compound (OBOC) combinatorial method is certainly the most accessible and powerful approach. Unfortunately, the use of cyclic peptides in OBOC libraries is limited by difficulties in sequencing hit compounds after the screening. Lacking a free N-terminal amine, Edman degradation cannot be used on cyclic peptides and complicated fragmentation patterns are obtained by tandem mass spectrometry (MS/MS). In this regard we have designed and developed new convenient ring-opening approaches to prepare and decode OBOC cyclic peptide libraries. Our strategy was to introduce a cleavable residue in the macrocycle and as a linker to allow linearization of peptides and their release from the beads for sequencing by MS/MS. First, amino acid residues sensible to nucleophiles, ultraviolet irradiation or cyanogens bromide were introduced in a model cyclic peptide. Afterward, the most promising residues were used to design and develop tandem ring-opening/cleavage approaches to decode OBOC cyclic peptide libraries. In the first approach a methionine residue was introduced in the macrocycle and as a linker to allow a simultaneous ring-opening and cleavage from the beads upon treatment with cyanogens bromide. In the second approach, a photosensitive residue was used in the macrocycle and as a linker for a dual ring-opening/cleavage upon UV irradiation. The linear peptide generated by these approaches can be efficiently sequenced by tandem mass spectrometry. Finally, an OBOC library has been prepared and screened against the HIV-1 Nef protein to identify selective ligands. The development of these methodologies will prompt the use of macrocyclic compounds in OBOC libraries and be an important contribution in medicinal chemistry for the discovery of protein ligands and the development of PPI inhibitors.
Download or read book Synthesis and Screening of Peptide Libraries for Biological Applications written by Thi Ba Trinh and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Combinatorial chemistry is a powerful tool in medicinal chemistry as well as chemical biology. In this work, we have applied combinatorial chemistry toward the analysis of peptide cyclization, specificity profiling of protein kinases and the identification of novel inhibitors against medicinally important protein targets.
Download or read book Combinatorial Synthesis Sequencing and Biological Applications of Peptide and Peptidomimetic Libraries written by Amit Thakkar and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: We have also successfully synthesized and sequenced support-bound cyclic peptoids, a novel class of compounds. By using a one-bead, two-compound approach, we have spatially segregated TentaGel microbeads (90 um) and synthesized a cyclic peptoid on the bead exterior to be used for biological screenings and a linear peptoid on the bead interior for sequencing by PED/MS. Cyclic peptoid libraries were used to investigate potential protein inhibitors and determine streptavidin ligands.
Download or read book De Novo Discovery of Synthetic Peptide Binders to Protein protein Interfaces written by Anthony James Quartararo and published by . This book was released on 2020 with total page 234 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protein-protein interactions (PPIs) play crucial roles in mediating normal cellular physiology, but their modulation has been historically challenging. PPIs tend to be intractable to small molecule inhibition, due to their wide and relatively featureless interfaces, and biologics are generally not viable for the approximately two-thirds of PPIs that take place in the intracellular milieu. Therefore, this class of target has been in many circles deemed undruggable. Peptides are an emerging therapeutic modality for disrupting PPIs. With proper engineering, they can engage proteins over large surface areas and in some cases be modified to access the cytosol. PPI-disrupting peptides are often discovered from highly diverse combinatorial libraries, through either genetic or chemical means. Genetically encoded approaches can reliably investigate enormous libraries (108–1013 members), typically via selection. However, despite progress in this area, these libraries are generally limited to natural chemical space. Peptides identified from such approaches therefore require extensive engineering to improve proteolytic stability and promote cell penetration, at the potential cost of potency. Synthetic libraries, on the other hand, are highly amenable to non-canonical amino acid incorporation and a wide variety of chemical modifications. However, these libraries are typically examined by screening, which in practice limits the diversities that can be explored to ~106. In this thesis, a magnetic bead-based affinity selection-mass spectrometry (AS-MS) workflow was developed to interrogate fully randomized, chemically accessed peptide libraries comprising up to 108 members with high fidelity. This approach takes advantage of recent advances in nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS)-based peptide sequencing, which facilitates high-confidence decoding of complex peptide mixtures. Starting with a model selection target, an anti-hemagglutinin monoclonal antibody, it was demonstrated that high enrichments of true binders could be achieved from a library comprising 106 members. The number of binders identified scaled in proportion to library diversity, as diversity was then increased from 106–108. Beyond 108, the complexity of isolated pools from single-pass selections became too great for reliable decoding. These results were applied to selections against biomedically-relevant targets, enabling the identification of p53-like binders to the oncogenic ubiquitin ligase MDM2, and a family of low-nanomolar affinity, [alpha]/[beta]-peptide-based binders to 14-3-3. Both sets of binders engage these targets at PPI epitopes. Finally, machine learning methods were developed to distinguish nonspecific from true binders identified by AS-MS, which we anticipate will greatly streamline future discovery efforts.
Download or read book Synthesis and Biological Applications of Glycoconjugates written by Olivier Renaudet and published by Bentham Science Publishers. This book was released on 2011 with total page 283 pages. Available in PDF, EPUB and Kindle. Book excerpt: The interactions between carbohydrates and proteins have been extensively explored in a wide range of physiological and pathological processes over several decades. The recent emergence of glycomics has strengthened this interest and notably contributed t
Download or read book Diversity Oriented Synthesis written by Andrea Trabocchi and published by John Wiley & Sons. This book was released on 2013-06-17 with total page 550 pages. Available in PDF, EPUB and Kindle. Book excerpt: Discover an enhanced synthetic approach to developing and screening chemical compound libraries Diversity-oriented synthesis is a new paradigm for developing large collections of structurally diverse small molecules as probes to investigate biological pathways. This book presents the most effective methods in diversity-oriented synthesis for creating small molecule collections. It offers tested and proven strategies for developing diversity-oriented synthetic libraries and screening methods for identifying ligands. Lastly, it explores some promising new applications based on diversity-oriented synthesis that have the potential to dramatically advance studies in drug discovery and chemical biology. Diversity-Oriented Synthesis begins with an introductory chapter that explores the basics, including a discussion of the relationship between diversity-oriented synthesis and classic combinatorial chemistry. Divided into four parts, the book: Offers key chemical methods for the generation of small molecules using diversity-oriented principles, including peptidomimetics and macrocycles Expands on the concept of diversity-oriented synthesis by describing chemical libraries Provides modern approaches to screening diversity-oriented synthetic libraries, including high-throughput and high-content screening, small molecule microarrays, and smart screening assays Presents the applications of diversity-oriented synthetic libraries and small molecules in drug discovery and chemical biology, reporting the results of key studies and forecasting the role of diversity-oriented synthesis in future biomedical research This book has been written and edited by leading international experts in organic synthesis and its applications. Their contributions are based on a thorough review of the current literature as well as their own firsthand experience developing synthetic methods and applications. Clearly written and extensively referenced, Diversity-Oriented Synthesis introduces novices to this highly promising field of research and serves as a springboard for experts to advance their own research studies and develop new applications.
Download or read book Beyond the Molecular Frontier written by National Research Council and published by National Academies Press. This book was released on 2003-03-19 with total page 238 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chemistry and chemical engineering have changed significantly in the last decade. They have broadened their scopeâ€"into biology, nanotechnology, materials science, computation, and advanced methods of process systems engineering and controlâ€"so much that the programs in most chemistry and chemical engineering departments now barely resemble the classical notion of chemistry. Beyond the Molecular Frontier brings together research, discovery, and invention across the entire spectrum of the chemical sciencesâ€"from fundamental, molecular-level chemistry to large-scale chemical processing technology. This reflects the way the field has evolved, the synergy at universities between research and education in chemistry and chemical engineering, and the way chemists and chemical engineers work together in industry. The astonishing developments in science and engineering during the 20th century have made it possible to dream of new goals that might previously have been considered unthinkable. This book identifies the key opportunities and challenges for the chemical sciences, from basic research to societal needs and from terrorism defense to environmental protection, and it looks at the ways in which chemists and chemical engineers can work together to contribute to an improved future.
Download or read book Combinatorial Chemistry and Technologies written by Stanislav Miertus and published by CRC Press. This book was released on 2005-04-12 with total page 597 pages. Available in PDF, EPUB and Kindle. Book excerpt: Several books on the market cover combinatorial techniques, but they offer just a limited perspective of the field, focusing on selected aspects without examining all approaches and integrated technologies. Combinatorial Chemistry and Technologies: Methods and Applications answers the demand for a complete overview of the field, covering all of the
Download or read book Chemical and Biological Synthesis written by Nick J Westwood and published by Royal Society of Chemistry. This book was released on 2018-08-16 with total page 339 pages. Available in PDF, EPUB and Kindle. Book excerpt: Synthetic chemistry plays a central role in many areas of chemical biology; utilising recent case studies, the goal of Chemical and Biological Synthesis is to highlight the full impact that the preparation of novel reagents can have in chemical biology. Covering the synthetic approaches that can be applied across the whole field of chemical biology, this book provides synthetic chemists with the broader context to which their work contributes and the biological questions that can be addressed through it. An ideal guide for postgraduate students and researchers in synthetic organic chemistry and chemical biology, Chemical and Biological Synthesis introduces synthetic techniques and methods to those who wish to incorporate synthesis for the first time in their biology-focused research programmes.
Download or read book The Organic Chemistry of Drug Design and Drug Action written by Richard B. Silverman and published by Elsevier. This book was released on 2012-12-02 with total page 650 pages. Available in PDF, EPUB and Kindle. Book excerpt: Standard medicinal chemistry courses and texts are organized by classes of drugs with an emphasis on descriptions of their biological and pharmacological effects. This book represents a new approach based on physical organic chemical principles and reaction mechanisms that allow the reader to extrapolate to many related classes of drug molecules. The Second Edition reflects the significant changes in the drug industry over the past decade, and includes chapter problems and other elements that make the book more useful for course instruction. New edition includes new chapter problems and exercises to help students learn, plus extensive references and illustrations Clearly presents an organic chemist's perspective of how drugs are designed and function, incorporating the extensive changes in the drug industry over the past ten years Well-respected author has published over 200 articles, earned 21 patents, and invented a drug that is under consideration for commercialization
Download or read book A Handbook for DNA Encoded Chemistry written by Robert A. Goodnow, Jr. and published by John Wiley & Sons. This book was released on 2014-04-28 with total page 495 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book comprehensively describes the development and practice of DNA-encoded library synthesis technology. Together, the chapters detail an approach to drug discovery that offers an attractive addition to the portfolio of existing hit generation technologies such as high-throughput screening, structure-based drug discovery and fragment-based screening. The book: Provides a valuable guide for understanding and applying DNA-encoded combinatorial chemistry Helps chemists generate and screen novel chemical libraries of large size and quality Bridges interdisciplinary areas of DNA-encoded combinatorial chemistry – synthetic and analytical chemistry, molecular biology, informatics, and biochemistry Shows medicinal and pharmaceutical chemists how to efficiently broaden available “chemical space” for drug discovery Provides expert and up-to-date summary of reported literature for DNA-encoded and DNA-directed chemistry technology and methods
Download or read book Combinatorial Chemistry and Technology written by Stanislav Miertus and published by CRC Press. This book was released on 1999-07-01 with total page 456 pages. Available in PDF, EPUB and Kindle. Book excerpt: "Provides comprehensive coverage of the current combinatorial methodologies and technologies employed for the design, synthesis, and screening of molecular ""libraries."" Features assessments of computer-assisted approaches to guiding library synthesis. Designed to satisfy the demand to create, produce in high yield and purity, and rapidly screen huge numbers of molecules."
