Leading experts provide a timely and comprehensive overview of the use of supramolecular systems in biomedical applications.
About the Author
Hans-Jorg Schneider has made many contributions in the field of supramolecular chemistry, in particular on mechanisms of molecular recognition including chemomechanical polymers, on cyclophane and cyclodextrin chemistry, and on synthetic enzyme and receptor analogs. The topics included synthetic allosteric complexes, polyamines, complexes with nucleotides and nucleic acids, with peptides, as well as artificial esterases and nucleases. Hans-Jorg Schneider has published over 260 papers, authored, co-authored or edited several books, including a textbook on supramolecular chemistry.
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Supramolecular Systems in Biomedical Fields
By Hans-Jörg Schneider
The Royal Society of ChemistryCopyright © 2013 The Royal Society of Chemistry
All rights reserved.
Universität des Saarlandes, FR Org. Chemie, D 66041 Saarbrücken
Non-covalent interactions dominate central parts of living systems, and provide a major role for chemistry in both healthcare and biotechnology. Modern synthetic methods have made it possible to prepare host compounds for virtually every target molecule, including those which function in the natural medium, water. In Chapter 13 Ramström et al. discuss how dynamic combinatorial chemistry can lead to an unlimited number of optimal ligands, inhibitors and potential drugs for biological targets. The action and development of drugs is the realm of medicinal chemistry, for which a large number of monographs and reviews is available. Nevertheless, the understanding of many biological functions, and particularly the rational design of new drugs or bioorganic self-assemblies, can take advantage of insights from the study of synthetic host–guest complexes. Thus, cation–π3 or anion–π4 interactions and their role in living systems first became apparent in artificial complexes; the same holds for many other interactions with aromatic moieties. Weak hydrogen bonds such as with C–H bonds or with organic halogens first became accessible to detailed elucidation with synthetic complexes; this applies also to, for instance, the interaction between halogen atoms and Lewis bases, and to dispersive forces. A remarkable limitation of Emil Fischer's lock-and-key principle was observed first with synthetic complexes, in which usually only 50% of the available space in a binding cavity is used; this rule was shown later to apply also to enzyme complexes.
Perhaps the most important aspect of using synthetic complexes is the possibility not only to elucidate the mechanism of all contributions to molecular recognition, but also to clarify geometric constraints — in particular to assign discrete energy values to them. This can help to develop energy scoring functions for drug design. It would have been tempting to devote some chapters to these mechanistic contributions for the understanding of non-covalent binding with biological systems. Instead the reader is pointed to the above-mentioned leading references; the present monograph tries to summarize practical applications of host–guest complexes in life sciences by means of chapters written by well-known specialists in applications, which can be grouped as follows.
From the beginning of supramolecular chemistry, analytical applications have played a major role. Supramolecular complexes can eventually lead to direct sensing of targets in the biological matrix without sample pretreatment, which often is still necessary in order to extract, isolate and concentrate the analytes of interest. In Chapter 2 Prins et al. illustrate how very high sensitivity can be achieved with amplification pathways combining catalysis and multivalency. Based on the use of synthetic catalysts containing recognition sequences one can, for example, detect DNA targets with a sensitivity down to 5 nM; with cationic polythiophenes forming triple helices with DNA targets, an affinity corresponding to 3x10-21 M detection limit can be reached. The use of host molecules which in sensors exhibit sensitive signals upon recognition of biomedically important analytes is discussed in Chapter 3 by Magri and Mallia with respect to metal ions, and in Chapter 4 by Schneider for organic and biological compounds. Magri describes the implementation of several interaction sites within hosts functioning also as logical gates; this leads to 'lab-on-a-molecule' devices. Confocal microscopy with fluorescent ligands allows, for example, imaging of Cd2+ ions in living cells. Sensing of organic analytes comprises — from metabolites, through alkaloids to drugs and toxins — a large variety of structures as illustrated with the typical examples presented in Chapter 4. For a highly sensitive and selective detection a myriad of synthetic host compounds has been designed, which bear suitable units for mostly optical signalling. In Chapter 14 Dickert and Mujahid show that molecular imprinting (MIP) techniques not only allow economical separations, but in particular highly selective recognition, which now extends also to antibodies, cells, viruses (including HIV) and even bacteria. They demonstrate that MIP receptors possess the potential to substitute natural antibodies, and allow detection of, for example, drug metabolites from complex matrices including blood and urine. Several chapters are centred not on particular targets or methods, but on host molecules which are used most often in biomedical applications, such as cyclodextrins (CDs; Chapter 5 by Ortiz Mellet et al.), calixarenes (Chapter 6 by Coleman and Perret), and cucurbiturils (CBs; Chapter 7 by Saleh et al.). Others host molecules such as crown ethers, cyclophanes, molecular tweezers, and porphyrins also play an increasingly important role in biomedical fields; they are mentioned in several chapters, in particular Chapter 4. Cyclodextrin-based assemblies can serve for the detection of pathogens or allergens, and are more cost-effective than the immunosorbent ELISA assay. CD–mannopyranosyl conjugates on a Ru(II) fluorescent core allowed identification of mannose-specific receptors presenting cells from Escherichia coli, for example. Cucurbituril derivatives have been used for the detection of amino acids, peptides, biogenic amines, alkaloids, or of cancer-associated nitrosamines, after immobilizaton, also on biochip sensors (chapters 7 and 12). As outlined in Chapter 12 by Hennig, such cucurbituril complexations can be used to monitor enzymatic reactions by supramolecular tandem assays. Hennig describes how for almost all enzyme classes fluorescence-based, label- and antibody-free supramolecular systems can be applied, based on chemosensors for products, membrane transport systems and tandem assays. Imaging with the help of supramolecular complexes, mostly involving fluorescence tomography, is discussed in Magri's contribution (Chapter 3) and also by Gupta and Pandey (Chapter 15); it is an emerging technique for the non-invasive, real-time visualization of biochemical events at the molecular level within living cells, tissues and/or intact organs. Gupta and Pandey show how nanoparticles allow the loading of multiple agents such as near-infrared fluorophores or radiotracers and photosensitizers for tumour detection. Chapter 10 by Schatz and Schüle highlights the recent progress in medical MRI diagnostics with suprmolecular metal complexes, in particular Gd3+ complexes, which has enabled the control of their relaxivity, possible toxicity and biodistribution, with tumour cells as target, for example. They also discuss optical imaging methods, including the use of supramolecular reporter units for selective imaging with Quantum dots and radioimaging with, for example, technetium complexes.
1.2 Interaction with Proteins and Nucleic Acids
As mentioned above, the action of drugs on proteins can be considered, medicinally, to be the most important part of supramolecular chemistry, but is treated elsewhere in many books. Closer to traditional supramolecular approaches is the use of macrocycles such as calixarenes modulating protein functions, as highlighted in Chapter 6 by Coleman and Perret, for cucurbiturils in Chapter 7 by Saleh et al., and for cyclodextrins, in Chapter 5 by Ortiz Mellet et al., and with some other hosts in Chapter 4 by Schneider. The supramolecular action even of small molecules can effectively compete with protein–protein interactions, which holds great promise for development of new drugs. Coleman and Perret illustrate the use of calixarenes for enzyme protection or activation and inhibition, as anticoagulants such as antithrombotic agents, specific binding to lectins, detection of, for instance, the pathogenic prion protein, and other 'theragnostic' applications. Nucleic acids lend themselves particularly well to studies of supramolecular complexation and drug interference in view of their regular structures and information content. In Chapter 8 Garcia-Espagna et al. show how synthetic polyamines offers new ways to differentiate groove binding and effect gene delivery; macrocyclic derivatives can lead to base flipping, to unfolding helices and to quadruplex stabilization in telomers. Metal complexes with allosteric control lead to new bioactive DNA ligands, and allow intriguing sequence selective cleavage, now partially surpassing the performance of natural restriction enzymes. The most established application of metal complexes concerns tumour therapy with platinum derivatives, for which recent developments are outlined in Chapter 9 by Aldrich-Wright and co-workers. They illustrate how addition of functional groups in such complexes can greatly enhance their efficiency — for example, by adding intercalating units — and hold promise with respect to biological targeting. New Pt(IV) instead of Pt(II) derivatives can help to solve toxicity problems; selectivity may be gained, for example, with ligands that bind to receptors that are overexpressed in tumours.
1.3 Drug Protection, Release and Targeting, Gene Delivery
Encapsulation of drugs in suitable host compounds was recognized early on as an efficient way to increase their water solubility and bioavailability. In particular cyclodextrins (Chapter 5 by Ortiz Mellet et al.), with already 30 different products on the market and more in clinical phases, can enhance drug absorption effciency, alter pharmacokinetics, and enhance stability against oxidation or enzymatic degradation. Nanocapsules with amphiphilic CDs have been shown to decrease toxicity of, for instance, cytostatic drugs. Polycationic cyclodextrins can act as on-viral gene vectors, multivalent CD conjugates can control carbohydrate–protein and cell surface interactions, and restore correct folding of peptides involved in diseases like Alzheimer's. Antitumour agents such as taxol derivatives have been targeted, for example, towards the mannose receptor of macrophages. As shown in Chapter 7 by Saleh et al., cucurbiturils recently emerged as carriers serving the same purposes as cyclodextrins, but often with different characteristics. Photocontrolled release of antibiotics is possible with a photo-base as auxiliary material. CB-based nanoparticles decorated non-covalently with, for example, a folate-spermidine conjugate can target human ovarian carcinoma cells. Experiments with various cancer cell lines have demonstrated that CBs are not toxic and retain the pharmacological activity of drug loads. Gupta and Pandey describe in Chapter 15 how selectivity in photodynamic therapy can be enhanced by binding the photosensitizer to molecular delivery systems or by conjugating sensitizers with targeting agents such as monoclonal antibodies, integrin antagonists, carbohydrates and other moieties with high affinity to target tissues. They show that biodegradable polyacrylamide-based nanoparticles hold much promise for both tumour detection and therapy. Gels formed by supramolecular aggregation of small molecules allow interesting biomedical applications. In Chapter 11 Escuder and Miravet show how implementation of, for example, antibiotics in such gels can enhance considerably their antibiotic activity. Peptide amphiphile-derived gels have already been used to treat a mouse model of spinal cord injury, demonstrating the amplification of properties associated to fibre formation — this is an example of tissue engineering. Hydrogel-based drug delivery can be used for oral, rectal, ocular, epidermal and subcutaneous application, which includes, for example, synthetic octapeptides that mimic natural hormones such as somatostatin.
Targeting in biological systems with the help of supramolecular complexation in macromolecules is also highlighted in Chapter 16 by Leblond et al. Polymers engineered with suitable binding functions can, by non-covalent interactions, mediate inflammation, block cellular receptors, immune responses or viral epitopes; they can damage bacterial membranes, inhibit adsorption and serve as toxin scavengers. For example, polymeric scavengers targeting bacterial toxins — virulence factors responsible for the symptoms associated with bacterial infections — are already being tested clinically. Polymeric binders can also help the body to fight against infections by targeting the pathogen: Virus epitopes can be treated with shielding polymers such as a polylysine dendrimer, impairing in this way the colonization capacity of viruses.
It is hoped that the selection of topics mentioned above provides a foretaste of the different chapters, which span a wide range of possible supramolecular applications in the life sciences.CHAPTER 2
Signalling Techniques in Supramolecular Systems
JEALEMY GALINDO MILLÁN AND LEONARD J. PRINS
Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Italy
A growing need exists for sensing techniques and strategies that permit accurate detection and quantification of analytes at ultralow concentrations. In the biomedical field, analyte detection with high sensitivity is vital since it permits the diagnosis of diseases at (very) early stages, leading to a higher chance of successful treatment. In addition, sensing techniques also play a key role in the detection of explosives in transportation systems (airports, railways systems, etc.), cargo and landmines, heavy metals in soil, water, environment and food and DNA in forensic sciences. Analyte detection limits are continuously being pushed down by the improvement of existing analytical technologies. In fact, the single molecule detection level can now be reached using various techniques, which include transmission electron microscopy (TEM), scanning electron microscopy (SEM), atomic force microscopy (AFM), surface plasmon resonance (SPR), surface enhanced Raman spectroscopy (SERS) and advanced fluorescence spectroscopy, the latter also permitting an application for sensing purposes. Nonetheless, the ultimate challenge in sensing is the development of a methodology that allows naked-eye detection of a single molecule in a complex mixture, that is, without the need for sophisticated instrumentation. In fact, the availability of simple and inexpensive techniques would favour an implementation in social contexts where advanced instrumentation or care centres are less available. A bottom-up approach to sensing is a perfect task for chemists, as it requires the ability to master molecular properties both on the molecular and collective levels. Such an analytical approach must evidently rely on signal amplification, implying that a weak signal originating from the analyte molecule is reinforced to a detectable intensity.
2.1.2 Signal Amplification in Nature
Nature does not have access to advanced instrumentation, but is nevertheless able to act very efficiently and selectively on weak impulses using very effective signal amplification pathways. This will be illustrated by two examples that cover two conceptually different approaches to signal amplification, which are also at the basis of the synthetic amplification schemes discussed in this chapter. Signal amplification in Nature occurs either through the analyte-triggered activation of a catalytic cascade leading towards the formation of multiple reporters (catalytic signal amplification) or the analyte-triggered alteration release of many reporters from a multivalent structure (multivalent amplification).
The mitogen-activated protein (MAP) kinase cascade is an excellent example of the power of catalytic signal amplification in Nature. A multi-tiered pathway is responsible for the activation of a catalytically multifunctional MAP kinase (MAPK), where each step consists of the phosphorylation of threonine/serine and/or tyrosine residues performed by an upstream kinase. In a typical three-tiered MAPK pathway, phosphorylation of threonine and tyrosine residues is carried out by MAP2 kinases which, in turn, are activated by phosphorylation of serine/threonine residues by MAP3 kinases. Signal amplification in such complex pathways occurs when the number of successive proteins exceeds that of its regulators, as has been observed for extracellular signal-regulated kinase (ERK 1/2) pathways. In this way, a single cell-surface binding event induced by an extracellular entity leads to a cascade of phosphorylations that harmonically regulate cell survival, apoptosis and mitosis, among other processes.
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Table of Contents
Introduction; Signalling Techniques in Supramolecular Systems; Metal Ion Sensing for Biomedical Uses; Complexation of Biomedically Important Organic Compounds; Cyclodextrins for Pharmaceutical and Biomedical Applications; Interactions of Calix[N]Arenes and Other Organic Supramolecular Systems with Proteins; Cucurbiturils in Drug Delivery and for Biomedical Applications; Nucleic Acids as Supramolecular Targets; Biomolecular Interactions of Platinum Complexes; Supramolecular Metal Complexes for Imaging and Radiotherapy; Supramolecular Gels for Pharmaceutical and Biomedical Applications; Supramolecular Enzyme Assays; Constitutional Dynamic Chemistry for Bioactive Compounds; Molecular Imprinted Polymers for Biomedical Applications; Supramolecular Approach for Tumor-Imaging and Photodynamic Therapy; Designing Polymeric Binders for Pharmaceutical Applications;