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The introduction of unnatural functionality in biological systems, coupled with detection using bioorthogonal chemical reactions, revolutionized the field of chemical biology by enabling the investigation of biological processes in live cells and simple organisms. However, the translation to complex organisms has led to less-than-optimal results with high background noise due to cross reactivity with activated reagents. This dissertation investigates the utilization of non-covalent chemistry and bioorthogonal host-guest pairs to obtain more efficient labeling of living systems. Complexation between a host and guest is diffusion-limited, hence can be efficient in dilute environments. The cucurbit[n]uril scaffold has been utilized to determine the minimum binding affinity required for efficient bioorthogonal complexation and investigate how guest size and charge affects the introduction of guests as unnatural metabolites. Carboranes, a cucurbit[7]uril guest class that can be removed "on demand" from the host cavity, were found compatible with metabolic glycoengineering and were successfully incorporated on the cell surface. The cucurbit[7]uril-carborane system serves as the first example of bioorthogonal complexation of a metabolically-incorporated guest and answers fundamental questions required for the further development of bioorthogonal host-guest pairs. Finally, work in expanding the properties of unnatural functionality that can be tolerated by biological systems led to the development of fluorescent guest molecules that could be used independently or in conjunction with molecular recognition tools to investigate living systems.Chapter One is a review on the expansion of chemical reporters beyond bioorthogonal chemistry by metabolic incorporation of alternative moieties with novel functions. These chemical reporters expand on our ability to study and manipulate biological processes with non-invasive methods. Chapters Two details the synthetic methodologies for functionalized cucurbit[7]urils. The two main synthetic approaches to obtaining mono-functionalized cucurbit[7]urils were investigated and cucurbit[7]uril-payload conjugates were synthesized that were used in the remaining work on bioorthogonal complexation described in this dissertation. Chapter Three describes the discovery of carboranes as cucurbit[7]uril guests and their derivatization to increase their binding affinity and aqueous solubility. Ortho-carborane is presented as an stimuli-responsive guest that allows recycling cucurbit[7]uril-solid support constructs through multiple payload isolation rounds in cell lysate. Chapter Four introduces bioorthogonal complexation, namely the labeling of cell-surfaces using host-guest chemistry. A variety of cucurbit[7]uril guests were labeled with a cucurbit[7]- uril-fluorescein conjugate to determine the minimum binding affinity required for bioorthogonal complexation. Metabolic incorporation of a cucurbit[7]uril guest is also presented as a sialic acid derivative on the cell surface that can be similarly labeled with cucurbit[7]uril-fluorophore conjugates. Chapters Five explores the functionality of cucurbit[7]uril guests that can be tolerated by the sialic acid biosynthetic pathway along with in vitro and in vivo methods to analyze and determine successful metabolic incorporation. Chapters Six outlines the development of fluorescent guest molecules that can serve as independent fluorophores or in conjuction with bioorthogonal complexation. The mechanism of luminescence is investigated and preliminary in cellulo data is presented that point towards potential applications.
This book offers a fresh perspective on how computational tools can aid the chemical biology research community and drive new research.
The importance of molecular recognition in chemistry and biology is reflected in a recent upsurge in relevant research, promoted in particular by high-profile initiatives in this area in Europe, the USA and Japan. Although molecular recognition is necessarily microscopic in origin, its consequences are de facto macroscopic. Accordingly, a text that starts with intermolecular interactions between simple molecules and builds to a discussion of molecular recognition involving larger scale systems is timely. This book was planned with such a development in mind. The book begins with an elementary but rigorous account of the various types of forces between molecules. Chapter 2 is concerned with the hydrogen bond between pairs of simple molecules in the gas phase, with particular reference to the preferred relative orientation of the pair and the ease with which this can be distorted. This microscopic view continues in chapter 3 wherein the nature of interactions between solute molecules and solvents or between two or more solutes is examined from the experimental standpoint, with various types of spectroscopy providing the probe of the nature of the interactions. Molecular recognition is central to the catalysis of chemical reactions, especially when bonds are to be broken and formed under the severe con straint that a specific configuration is to result, as in the production of enan tiotopically pure compounds. This important topic is considered in chapter 4.
The rapid development of efficient computational tools has allowed researchers to tackle biological problems and to predict, analyse and monitor, at an atomic level, molecular recognition processes. This book offers a fresh perspective on how computational tools can aid the chemical biology research community and drive new research. Chapters from internationally renowned leaders in the field introduce concepts and discuss the impact of technological advances in computer hardware and software in explaining and predicting phenomena involving biomolecules, from small molecules to macromolecular systems. Important topics from the understanding of biomolecules to the modification of their functions are addressed, as well as examples of the application of tools in drug discovery, glycobiology, protein design and molecular recognition. Not only are the cutting-the-edge methods addressed, but also their limitations and possible future development. For anyone wishing to learn how computational chemistry and molecular modelling can provide information not easily accessible through other experimental methods, this book will be a valuable resource. It will be of interest to postgraduates and researchers in the biological and chemical sciences, medicinal and pharmaceutical chemistry, and theoretical chemistry.
With its exploration of the scientific and technological characteristics of systems exploiting molecular recognition between synthetic materials, such as polymers and nanoparticles, and biological entities, this is a truly multidisciplinary book bridging chemistry, life sciences, pharmacology and medicine. The authors introduce innovative biomimetic chemical assemblies which constitute platforms for recruitment of cellular components or biological molecules, while also focusing on physical, chemical, and biological aspects of biomolecular recognition. The diverse applications covered include biosensors, cell adhesion, synthetic receptors, cell patterning, bioactive nanoparticles, and drug design.
A new perspective on the design of molecular therapeutics is emerging. This new strategy emphasizes the rational complementation of functionality along extended patches of a protein surface with the aim of inhibiting protein/protein interactions. The successful development of compounds able to inhibit these interactions offers a unique chance to selectively intervene in a large number of key cellular processes related to human disease. Protein Surface Recognition presents a detailed treatment of this strategy, with topics including: an extended survey of protein-protein interactions that are key players in human disease and biology and the potential for therapeutics derived from this new perspective the fundamental physical issues that surround protein-protein interactions that must be considered when designing ligands for protein surfaces examples of protein surface-small molecule interactions, including treatments of protein-natural product interactions, protein-interface peptides, and rational approaches to protein surface recognition from model to biological systems a survey of techniques that will be integral to the discovery of new small molecule protein surface binders, from high throughput synthesis and screening techniques to in silico and in vitro methods for the discovery of novel protein ligands. Protein Surface Recognition provides an intellectual “tool-kit” for investigators in medicinal and bioorganic chemistry looking to exploit this emerging paradigm in drug discovery.
Reasoning in terms of molecular recognition may be traced back to Emil Fischer, who practiced the art of chemistry at Humboldt University in Prussian Berlin a century ago. Today, it is clearly recognized that molecular recognition impacts and determines all life processes. It has become a key research field in both chemistry and biology and the emerging interface of what now is being called "chemical biology". The technological advances derived from this knowledge are particularly important, diverse, and directly evident in the pharmaceutical industry. Under the auspices of the Ernst Schering Research Foundation, a workshop held in Berlin in February 1998 addressed novel basic developments of potential relevance to drug research efforts. A balance of timely research topics in molecular recognition is presented in the lectures delivered by a multidisciplinary international panel of renowned scholars and documented in this volume.