Differential receptor arrays and assays for solution-based molecular recognition

Nature has inspired an emergent supramolecular field of synthetic receptor arrays and assays for the pattern-based recognition of various bioanalytes and metal species. The synthetic receptors are not necessarily selective for a particular analyte, but the combined signal response from the array is diagnostic for the analyte. This tutorial review describes recent work in the literature for this emerging supramolecular field and details basic array and assay design principles. We review the analytes targeted, signaling types used, and pattern recognition.Developing specific receptors for the solution-based analysis of complex analytes and mixtures is a daunting task. A solution to this difficult task has been inspired by nature's use of arrays of receptors in the senses of taste and smell. An emerging field within supramolecular chemistry is the use of synthetic and readily available receptors in array formats for the detection of analytes in solution. Each receptor in a differential array does not necessarily have selectivity for a particular analyte, but the combined fingerprint response can be extracted as a diagnostic pattern visually, or using chemometric tools. This new genre of molecular recognition is advancing rapidly with several groups developing novel array platforms and receptors.     

Nanoparticles: scaffolds for molecular recognition

Monolayer and mixed-monolayer protected clusters (MPCs and MMPCs) have great potential to combine molecular functionality with the intrinsic properties of nanometer-sized scaffolds. This synergy can be used to create complex functional devices, including redox-active, electronic, or magnetic storage devices, solution-based sensors, and highly efficient catalysts. This review outlines some of the recent developments in nanoscale receptors based on synthetic and nonbiological recognition elements. In these nanoparticle systems, molecular recognition is achieved by covalent attachment of receptors on the nanoparticles coupled with noncovalent interactions to target substrates. Synthetic host-guest systems, hydrogen bonding, change in redox states, pi-pi stacking, rotaxane formation, and ion recognition are the main topics covered in this review.     

Molecular Receptors for Recognition and Sensing of Nucleotides

Nucleotides are constituents of nucleic acids and they have a variety of functions in cellular metabolism. Synthetic receptors and sensors are required to reveal the role of nucleotides in living organisms and mechanisms of signal transduction events. In recent years, a large number of nucleotide-selective synthetic receptors have been devised, which utilize different molecular designs and sensing mechanisms. This Minireview presents recent progress in the design of synthetic molecular receptors for selective recognition of nucleotides in aqueous solution. The binding properties of receptors and the origins of their selectivity for a particular nucleotide are discussed.     

Molecular recognition: from solution science to nano/materials technology

In the 25 years since its Nobel Prize in chemistry, supramolecular chemistry based on molecular recognition has been paid much attention in scientific and technological fields. Nanotechnology and the related areas seek breakthrough methods of nanofabrication based on rational organization through assembly of constituent molecules. Advanced biochemistry, medical applications, and environmental and energy technologies also depend on the importance of specific interactions between molecules. In those current fields, molecular recognition is now being re-evaluated. In this review, we re-examine current trends in molecular recognition from the viewpoint of the surrounding media, that is (i) the solution phase for development of basic science and molecular design advances; (ii) at nano/materials interfaces for emerging technologies and applications. The first section of this review includes molecular recognition frontiers, receptor design based on combinatorial approaches, organic capsule receptors, metallo-capsule receptors, helical receptors, dendrimer receptors, and the future design of receptor architectures. The following section summarizes topics related to molecular recognition at interfaces including fundamentals of molecular recognition, sensing and detection, structure formation, molecular machines, molecular recognition involving polymers and related materials, and molecular recognition processes in nanostructured materials.     

Optical sensing based on analyte recognition by enzymes,carriers and molecular interactions

Despite the tremendous variety of methods suitable for sensing applications, we face the fact that chemical sensors displaying sensitivity, selectivity and reversibility are still scarce and are mostly confined to low-molecular-weight species. Obviously, it is not the lack of optical (or other) transduction methods that limit the performance of present day sensor desingns, but rather the insufficient selectivity of the recognition process, particularly in the field of sensors for organic and bioorganic species. The use of enzymes, ion carriers and natural or synthetic receptor/carriers which can under go specific interactions with the species to be recognized (such as through hydrogen bonding or charge-transfer interaction) can result in specific recognition and, consequently, sensing. Examples for optical sensing schemes for clinically or biologically important species including enzyme substrates, metabolites, drugs, alkali and ammonium ions and other will be given. In enzyme-based sensors various options exist: depending on which species is immobilized, assays for substrates (such as glucose, ethanol, lactate or creatine), enzymes (such as esterases) or inhibitors (such as organophosphates) can be designed. In addition, the intrinsic optical properties of certain enzymes, coenzymes or metabolites can be utilized for sensing purposes, a fact that presents an interesting alternative to enzyme sensors with chemical transducers.Notwithstanding the selectivity of biocatalytic sensors, their stability and sensitivity is moderate. Bioorganic synthetic molecules which can recognize and reversibly bind other species offer an attractive alternative, particularly in terms of stability. However, quite a different situation is found in such cases because receptors, in contrast to enzymes, do not “digest” their substrates. Hence, while the steady-state response in enzyme-based sensors is a result of kinetic equilibration, substrate binding in non-metabolizing receptors results in thermodynamic equilibration. However, most existing receptors (except antibodies) lack the unique specificity of enzymes. On the other side, new bioorganic molecules and stable receptor/carriers along with polymer materials of proper permeation selectivity can help to overcome current limitations of protein-based systems. Neutral ion carriers, which may be considered as ion receptors, are a useful example of sometimes highly specific recognition/carrier molecules with excellent stability. Unfortunately, no receptor /carrier molecules of similar specificity do exist yet for most other organic and clinical parameters of interest. There is an obvious need for new and stable molecules suitable for specific recognition of low-molecular weight organic species.We will report on the use of such new receptor/carrier molecules, the respective sensor materials, and how the process of recognition can be coupled to optical transduction. Such receptors/carriers also allow other kinds of discriminations: if, for instance, it is enantio-selective (i.e. preferably binds one species out of a pair of optical isomers), a fairly specific recognition of enantiomers of biogenic amines (such as some drugs and biogenic amines) will become possible. Specific examples will also be given of new types of sensors based on recognition by charge-transfer interaction, through-space interaction and hydrogen bonding, with fair specificity for thiamine, penicilline, nitrate, salicylate and cholic acids. Finally, current problems and the significant challenges for sensors research in the 1990s will be discussed.     

Selective Recognition of Amino Acids and Peptides by Small Supramolecular Receptors

To this day, the recognition and high affinity binding of biomolecules in water by synthetic receptors remains challenging, while the necessity for systems for their sensing, transport and modulation persists. This problematic is prevalent for the recognition of peptides, which not only have key roles in many biochemical pathways, as well as having pharmacological and biotechnological applications, but also frequently serve as models for the study of proteins. Taking inspiration in nature and on the interactions that occur between several receptors and peptide sequences, many researchers have developed and applied a variety of different synthetic receptors, as is the case of macrocyclic compounds, molecular imprinted polymers, organometallic cages, among others, to bind amino acids, small peptides and proteins. In this critical review, we present and discuss selected examples of synthetic receptors for amino acids and peptides, with a greater focus on supramolecular receptors, which show great promise for the selective recognition of these biomolecules in physiological conditions. We decided to focus preferentially on small synthetic receptors (leaving out of this review high molecular weight polymeric systems) for which more detailed and accurate molecular level information regarding the main structural and thermodynamic features of the receptor biomolecule assemblies is available.     

Capturing molecules with templated materials--analysis and rational design of molecularly imprinted polymers

The creation of synthetic tailor-made receptors capable of recognizing desired molecular targets with high affinity and selectivity is a persistent long-term goal for researchers in the fields of chemical, biological, and pharmaceutical research. Compared to biomacromolecular receptors, these synthetic receptors promise simplified production and processing, less costs, and more robust receptor architectures. During recent decades, molecularly imprinted polymers (MIPs) are widely considered mimics of natural molecular receptors suitable for a diversity of applications ranging from biomimetic sensors, to separations and biocatalysis.A remaining challenge for the next generation of MIPs is the synthesis of deliberately designed and highly efficient receptor architectures suitable for recognizing biologically relevant molecules, for which natural receptors are either not prevalent, or difficult to isolate and utilize. Hence, this review discusses recent advances in synthetic receptor technology for biomolecules (e.g. drugs, amino acids, steroids, proteins, entire cells, etc.) via molecular imprinting techniques. Surface imprinting methods and epitope imprinting approaches have been introduced for protein recognition at imprinted surfaces. Imprinting techniques in aqueous solution or organic-water co-solvents have been introduced avoiding denaturation of biomolecules during MIP synthesis. In addition, improved bioreactivity of entire enzyme or active site mimics generated by molecular imprinting will be highlighted. Finally, the emerging importance of molecular modeling and molecular dynamics studies detailing the intermolecular interactions between the template species, the porogenic solvent molecules, and the involved monomer and cross-linker in the pre-polymerization solution will be addressed yielding a rational approach toward next-generation MIP technology.     

Opportunities to improve selectivity of determining oxidoreductase substrate using artificial receptors

The review considers the prospects of using molecular recognition by artificial receptors (macro-cyclic compounds and molecularly imprinted polymers) to create sensors for the determination of biologically active compounds, i.e., substrates of oxidoreductases, in samples with complex matrices. The data on the production, properties, and application of complexes of the indicated artificial receptors with the analytes, i.e., organic compounds of different classes, for analytical purposes have been systemized for the first time. Special attention is focused on the discussion of approaches that ensure the specificity of the receptor due to molecular recognition.     

Luminescent lanthanide complexes as analytical tools in anion sensing, pH indication and protein recognition

Although lanthanide complexes are recently used in luminescence labeling of bio-targets, this review focuses on sensing profiles of synthetic and biological lanthanide complexes. Rational design and combinatorial screening approaches toward synthetic lanthanide complexes applicable as luminescent sensing materials are described. Iron-carrying transferrin and ferritin proteins further form lanthanide complexes working as pH indicators and protein recognition reagents.     

Recognition of proteins and peptides: Rational development of molecular imprinting technology

The creation of tailor-made receptors which are able to recognize molecular targets with high affinity and selectivity has attracted much attention in the field of chemistry, physics, and biology. Molecular imprinting has proved to be an effective technique for generating specific recognition sites in synthetic polymers. The synthesis of molecular imprinted polymers specific for proteins and peptides has been a focus for many scientists working in the area of molecular recognition, since the creation of synthetic polymers that can specifically recognize biomacromolecules is a very challenging but potentially extremely rewarding work. These polymers with specificity for biological macromolecules have considerable potential for applications in the areas of solid phase extraction, catalysis, medicine, clinical analysis, drug delivery, environmental monitoring, and sensors. In this review, the authors discuss the developed approaches associated with the imprinting of peptides and proteins, and provide an overview of the significant progress achieved within this field. Finally, the possible mechanism of the molecular imprinting and recognition has been discussed.     

Molecular recognition at the gas-solid interface: a powerful tool for chemical sensing

This tutorial review deals with the design of molecular receptors capable of molecular recognition at the gas-solid interface, to be used as selective layers in gas sensors. The key issue of specific versus nonspecific binding in the solid layer is discussed in terms of cavity inclusion and layer morphology. The combined use of mass spectrometry and crystal structure analysis provide accurate information on type, number, geometry and strength of receptor-analyte interactions in the gas phase and in the solid state. From these data, the gas sensing properties of a given receptor toward a single class of analytes can be anticipated.     

Short peptides as biosensor transducers

This review deals with short peptides (up to 50 amino acids) as biomimetic active recognition elements in sensing systems. Peptide-based sensors have been developed in recent years according to different strategies. Synthetic peptides have been designed on the basis of known interactions between single or a few amino acids and targets, with attention being paid to the presence of peptide motifs known to allow intermolecular self-organization of the sensing peptides over the sensor surface. Sensitive and sophisticated sensors have been obtained in this way, but the use of designed peptides is limited by severe difficulties in their in silico design. Short peptides from random phage display have been selected in a random way from large, unfocussed, and often preexisting and commercially available phage display libraries, with no design elements. Such peptides often perform better than antibodies, but they are difficult to select when the target is a small molecule because of the need to immobilize it with considerable modifications of its structure. Artificial, miniaturized receptors have been obtained from the reduction of the known sequence of a natural receptor down to a synthesizable and yet stable one. Alternatively, binding sites have been created over a designed, stable peptide scaffold. Short peptides have also been used as active elements for the detection of their own natural receptors: pathogenic bacteria have been detected with antimicrobial and cell-penetrating peptides, but key challenges such as detection of bacteria in real samples, improved sensitivity, and improved selectivity have to be faced. Peptide substrates have been conjugated to fluorescent quantum dots to obtain disposable sensors for protease activity with high sensitivity. Ferrocene–peptide conjugates have been used for electrochemical sensing of protease activity.     

Von der molekularen Erkennung zum Design neuer Wirkstoffe: Peptiden auf den Leib geschneidert

The molecular recognition of peptides or peptide fragments by synthetic receptor molecules is of great importance for the design of biosensors, the targeting of cellular processes and hence the development of new therapeutics. Unfortunately, our general understanding of non‐covalent interactions is no yet elaborated enough to create a tailor made receptor starting from zero. One possible approach is therefore to mimic the principles and binding motifs found in nature and further evolve them in to effective receptor molecules using either rational structure variations or a more random combinatorial synthesis. The usefullness and prospective potential of these approaches is illustrated with two case studies showing how one tries to find new strategies to fight bacterial infections and cancer with the help of artificial peptide receptors.     

Triphenylene: A versatile molecular receptor

Since the late seventies, the search for new molecular receptors has been constant in perfecting the affinity and selectivity of recognition in different media. At present, a renewed interest in (host:guest) chemistry focuses on the molecular detection of specific targets such as biological, pollutant, toxic or explosive species. This review of triphenylene-based receptors outlines their recent contribution to molecular recognition. Two main structural approaches were investigated to transform a simple triphenylene moiety into a host for neutral aromatic compounds or cations, by tailoring multivalent molecules provided with or without a flatten cavity. The properties of different receptors are presented along with the latest synthetic methods to prepare high-value triphenylenes and the perspectives in the field of sensing. In addition, the role of functionalized triphenylenes in extended (host:guest) systems is illustrated by the main examples of discotic liquid crystals and porous coordination polymers involving this polyaromatic compound.     

杯芳烃类受体的分子识别作用研究进展

综述了杯芳烃类人工受体的分子识别作用的研究进展。主要介绍通过非共价键作用引起的识别-配合与识别-催化作用。     

Biological applications of amide and amino acid containing synthetic macrocycles

ABSTRACT

Amino acid derived macrocycles with elaborate well-defined stereochemistry are a unique class of compounds that have been isolated from natural sources. Macrocycles like cyclosporine, octreotide, and valinomycin have been used in multiple applications, like drugs or ion sensors. Chemists have long been fascinated by the unique molecular recognition capabilities of these macrocycles and tried to design synthetic analogs with similar functions. This article is focused on reviewing current research on amide and amino acid containing macrocycles that have been developed in research laboratories for biological recognition, specifically for anion sensing, ion transport, carbohydrate sensing, and peptide sensing.     

Nanopore‐Based Confined Spaces for Single‐Molecular Analysis

The field of nanopore sensing at the single‐molecular level is in a “boom” period. Such nanopores, which are either composed of biological materials or are fabricated from solid‐state substrates, offer a unique confined space that is compatible with the single‐molecular scale. Under the influence of an electrical field, such single‐biomolecular interfaces can read single‐molecular information and, if appropriately fine‐tuned, each molecule plays its individual ionic rhythm to compose a “molecular symphony”. Over the past few decades, many research groups have worked on nanopore‐based single‐molecular sensors for a range of thrilling chemical and clinical applications. Furthermore, for the past decade, we have also focused on nanopore‐based sensors. In this Minireview, we summarize the recent developments in fundamental research and applications in this area, along with data algorithms and advances in hardware, which act as infrastructure for the electrochemical analysis.     

Study of the physicochemical properties of tulobuterol dry syrups using taste and smell sensors

The purpose of the present study was to evaluate the taste and smell of Tulobuterol Dry Syrup (TB-DS) in its original form (formulation A) and generic form (formulations B and C) by means of gustatory sensation tests and taste and smell sensors. In addition, the physicochemical properties of the syrups in a solid state were compared. Evaluation of sweetness with a powdered sample revealed significant differences between formulation A and formulation B and between formulation B and formulation C. In contrast, the results of principal component analysis (PCA) with a taste sensor revealed differences in principal component 1 (PC 1) among formulations A, B, and C. Smell sensor measurement of powdered samples revealed differences in products in terms of only PC 1, but these results were not related to the results of gustatory sensation testing with a smell sensor. Measurement of particle size distribution and scanning electron microscopy revealed differences in the particle diameter and particle surface shape for each product. Formulation B had the strongest absorption in the near-infrared spectrum, followed by formulation A and then formulation C. Accordingly, differences in preparations were presumably caused by variations in manufacturing specifications, such as types of additives and their content and coating methods used. In other words, the characteristics of each product were revealed by evaluation of their physical properties, sensing of taste and smell, and human gustatory sensation tests.