Peptide-nanowire hybrid materials for selective sensing of small molecules

The development of a miniaturized sensing platform for the selective detection of chemical odorants could stimulate exciting scientific and technological opportunities. Oligopeptides are robust substrates for the selective recognition of a variety of chemical and biological species. Likewise, semiconducting nanowires are extremely sensitive gas sensors. Here we explore the possibilities and chemistries of linking peptides to silicon nanowire sensors for the selective detection of small molecules. The silica surface of the nanowires is passivated with peptides using amide coupling chemistry. The peptide/nanowire sensors can be designed, through the peptide sequence, to exhibit orthogonal responses to acetic acid and ammonia vapors, and can detect traces of these gases from "chemically camouflaged" mixtures. Through both theory and experiment, we find that this sensing selectivity arises from both acid/base reactivity and from molecular structure. These results provide a model platform for what can be achieved in terms of selective and sensitive "electronic noses."     

Supramolecular Strategies for Controlling Reactivity within Confined Nanospaces

Nanospaces are ubiquitous in the realm of biological systems and are of significant interest among supramolecular chemists. Understanding chemical behavior within nanospaces offers new perspectives on biological phenomena in nature and opens the way to highly unusual and selective forms of catalysis. Supramolecular chemistry exploits weak, yet effective, intermolecular interactions such as hydrogen bonding, metal‐ligand coordination, and the hydrophobic effect to assemble nano‐sized molecular architectures, providing reactions with remarkable rate acceleration, substrate specificity, and product selectivity. In this minireview, the focus is on the strategies that supramolecular chemists use to emulate the efficiency of biological processes, and elucidating how chemical reactivity is efficiently controlled within well‐defined nanospaces. Approaches such as orientation and proximity of substrate, transition‐state stabilization, and active‐site incorporation will be discussed.     

Recent developments in the detection of singlet oxygen with molecular spectroscopic methods

Singlet oxygen is a unique reactive oxygen species, as its chemical reactivity derives from its characteristic electronically-excited state. The involvement of singlet oxygen in many important atmospheric, physical, chemical, biological, and therapeutic processes has attracted intense research interest in recent years. The detection and the quantification of singlet oxygen are very important for understanding its mechanism of action in various processes.Due to its highly reactive nature, singlet oxygen has very few direct methods of determination. Only molecular phosphorescence at 1270 nm has been utilized. Indirect methods using spectrophotometric, fluorescent or chemiluminescent probes have therefore been extensively studied.This review reflects recent developments in singlet-oxygen detection with molecular spectroscopic methods. We begin with a brief introduction of the basic properties, the production and the applications of singlet oxygen. With this background information, we review the four molecular spectroscopic methods (i.e., emission, spectrophotometry, fluorescence and chemiluminescence). We pay special attention to attractive chemical probes with high selectivity and sensitivity in quantifying singlet oxygen.     

Synthetic Strategies for the Selective Functionalization of Carbon Nanodots Allow Optically Communicating Suprastructures

The surface of Carbon Nanodots (CNDs) stands as a rich chemical platform, able to regulate the interactions between particles and external species. Performing selective functionalization of these nanoscale entities is of practical importance, however, it still represents a considerable challenge. In this work, we exploited the organic chemistry toolbox to install target functionalities on the CND surface, while monitoring the chemical changes on the material's outer shell through nuclear magnetic resonance spectroscopy. Following this, we investigated the use of click chemistry to covalently connect CNDs of different nature en-route towards covalent suprastructures with unprecedent molecular control. The different photophysical properties of the connected particles allowed their optical communication in the excited state. This work paves the way for the development of selective and addressable CND building blocks which can act as modular nanoscale synthons that mirror the long-established reactivity of molecular organic synthesis.     

Chemoproteomic Evaluation of the Polyacetylene Callyspongynic Acid

Polyacetylenes are a class of alkyne‐containing natural products. Although potent bioactivities and thus possible applications as chemical probes have already been reported for some polyacetylenes, insights into the biological activities or molecular mode of action are still rather limited in most cases. To overcome this limitation, we describe the application of the polyacetylene callyspongynic acid in the development of an experimental roadmap for characterizing potential protein targets of alkyne‐containing natural products. To this end, we undertook the first chemical synthesis of callyspongynic acid. We then used in situ chemical proteomics methods to demonstrate extensive callyspongynic acid‐mediated chemical tagging of endoplasmic reticulum‐associated lipid‐metabolizing and modifying enzymes. We anticipate that an elucidation of protein targets of natural products may serve as an effective guide to the development of subsequent biological assays that aim to identify chemical phenotypes and bioactivities.     

Artificial Allosteric Receptors

Cooperative effects in the binding of two or more substrates to different binding sites of a receptor that are a result of a conformational change caused by the binding of the first substrate—also referred to as the effector—are called allosteric effects. In biological systems, allosteric regulation is a widely used mechanism to control the function of proteins and enzymes in cellular metabolism. Inspired by this a lot of efforts have been made in supramolecular chemistry to implement this concept into artificial systems to control functions as molecular recognition, signal amplification, or even reactivity and catalysis. This review gives an up‐to‐date overview over the different approaches that have been reported ever since the first examples from the late 1970s/early 1980s. It covers both homo‐ and heterotropic examples and is divided according to the nature of the effector—cationic, anionic, or neutral—effectors and systems that use combinations of those.     

Tandem Payne/Dakin Reaction: A New Strategy for Hydrogen Peroxide Detection and Molecular Imaging

Hydrogen peroxide (H₂O₂) has been recognized as one of the most significant ROS (reactive oxygen species) in human health and disease. Because of the intrinsic attributes of H₂O₂—such as its low reactivity under physiological pH—it is exceedingly challenging to develop small‐molecule fluorescent probes with high selectivity and sensitivity for visualization of H₂O₂ in an intricate biological milieu. To address this gap, a rationally designed tandem Payne/Dakin reaction is reported that is specific to molecular recognition of H₂O₂. New H₂O₂ probes based on this unique chemical strategy can be easily synthesized by a general coupling reaction, and the practical applicability of those probes has been confirmed by the visualization of endogenously produced H₂O₂ in living cells. In particular, starvation‐induced H₂O₂ production in mouse macrophages has been detected by the novel probe in both confocal imaging and flow cytometry. This tandem Payne/Dakin reaction provides a basis for developing more sophisticated molecular tools to interrogate H₂O₂ functions in biological phenomena.     

Near‐IR Photochemistry for Biology: Exploiting the Optical Window of Tissue

Photoactive molecules enable much of modern biology and biochemistry—a vast library of fluorescent chromophores is used to track and label cellular structures and macromolecules. However, photochemistry is better known to the synthetic or physical organic chemist as a “light switch” that turns on unusual excited‐state reactivity, isomerization, or dynamic adjustment of structure. This review details a rapidly growing approach to biophotochemistry that uses low‐energy near‐IR wavelengths not only for imaging, but also for close spatial control over chemical switching events in biosystems. Emphasis is placed on topics of biomedical interest: release of gaseous biological messengers, uncaging of drugs, nano‐therapeutics, and modification of biomaterials.     

Enzyme Activity by Design: An Artificial Rhodium Hydroformylase for Linear Aldehydes

Artificial metalloenzymes (ArMs) are hybrid catalysts that offer a unique opportunity to combine the superior performance of natural protein structures with the unnatural reactivity of transition‐metal catalytic centers. Therefore, they provide the prospect of highly selective and active catalytic chemical conversions for which natural enzymes are unavailable. Herein, we show how by rationally combining robust site‐specific phosphine bioconjugation methods and a lipid‐binding protein (SCP‐2L), an artificial rhodium hydroformylase was developed that displays remarkable activities and selectivities for the biphasic production of long‐chain linear aldehydes under benign aqueous conditions. Overall, this study demonstrates that judiciously chosen protein‐binding scaffolds can be adapted to obtain metalloenzymes that provide the reactivity of the introduced metal center combined with specifically intended product selectivity.     

Polymers for Anion Recognition and Sensing

In biological systems, the selective and high‐affinity recognition of anionic species is accomplished by macromolecular hosts (anion‐binding proteins) that have been “optimized” through evolution. Surprisingly, it is only recently that chemists have systematically attempted to develop anion‐responsive synthetic macromolecules for potential applications in medicine, national security, or environmental monitoring. Recent results indicating that unique features of polymeric systems such as signal amplification, multivalency, and cooperative behavior may be exploited productively in the context of anion recognition and sensing are documented. The wide variety of interactions—including Lewis acid/base, ion‐pairing, and hydrogen bonding—that have been employed for this purpose is reflected in the structural diversity of anion‐responsive macromolecules identified to date.     

Determination of the Orientation of Pendants on Rigid‐Rod Polymers

Bis‐norbornene and bis‐cyclobutene with different kinds of linkers have been extensively used for the synthesis of double stranded ladderphanes under ruthenium‐ or molybdenum‐catalyzed ring opening metathesis polymerization (ROMP) conditions. The key to the success relies on the selective formation of comb‐like polynorbornenes or polycycloubtenes, where pendants are all aligned towards similar direction. This minireview summarizes various methods (chemical methods, spectroscopic means, and nonlinear optical measurements) for determining the comb‐like conformations of pendants on these rigid‐rod polymers. The approach is based on the proximal relationship between adjacent pendants. Interactions between these adjacent pendants would enable a change in chemical reactivity     

Quantitative analysis of N‐acylphosphatidylethanolamine molecular species in rat brain using solid‐phase extraction combined with reversed‐phase chromatography and tandem mass spectrometry

A novel method for the sensitive and selective identification and quantification of N‐acylphosphatidylethanolamine molecular species was developed. Samples were prepared using a combination of liquid–liquid and solid‐phase extraction, and intact N‐acylphosphatidylethanolamine species were determined by reversed‐phase high‐performance liquid chromatography coupled to positive electrospray tandem mass spectrometry. As a result of their biological functions as precursors for N‐acylethanolamines and as signaling molecules, tissue concentrations of N‐acylphosphatidylethanolamines are very low, and their analysis is additionally hindered by the vast excess of other sample components. Our sample preparation methods are able to selectively separate the analytes of interest from any expected biological interferences. Finally, the highest selectivity is achieved by coupling chromatographic separation and two N‐acyl chain specific selected reaction monitoring scans per analyte, enabling identification of both the N‐acyl chain and the phosphatidylethanolamine moiety. The validated method is suitable for the reliable quantification of N‐acylphosphatidylethanolamine species from rat brain with a lower limit of quantification of 10 pmol/g and a linear range up to 2300 pmol/g. In total, 41 N‐acylphosphatidylethanolamine molecular species with six different N‐acyl chains, amounting to a total concentration of 3 nmol/g, were quantified.     

Tosyl esters of cinchonidine and cinchonine alkaloids: the structure–reactivity relationship in the hydrolysis to 9‐epibases

In the crystal structures of the diastereoisomers of O‐tosylcinchonidine [(9R)‐cinchon‐9‐yl 4‐methylbenzenesulfonate], (I), and O‐tosylcinchonine [(9S)‐cinchon‐9‐yl 4‐methylbenzenesulfonate], (II), both C₂₆H₂₈N₂O₃S, both molecules are in an anti‐closed conformation and, in each case, the position of the aryl ring of the tosylate system is influenced by an intramolecular C—H...O hydrogen bond. The molecular packing in (I) is influenced by weak intermolecular C—H...O and C—H...π interactions. The crystal structure of (II) features C—H...π interactions and van der Waals forces only. The computational investigations using RHF/6–31G** ab initio and AM1 semi‐empirical methods performed for (I) and (II) and their protonated species show that the conformational and energetic parameters of the molecules are correlated with differences in their reactivity in hydrolysis to the corresponding 9‐epibases.     

Mechanistic Insights into the Luminescent Sensing of Organophosphorus Chemical Warfare Agents and Simulants Using Trivalent Lanthanide Complexes

Organophosphorus chemical warfare agents (OP CWAs) are potent acetylcholinesterase inhibitors that can cause incapacitation and death within minutes of exposure, and furthermore are largely undetectable by the human senses. Fast, efficient, sensitive and selective detection of these compounds is therefore critical to minimise exposure. Traditional molecular‐based sensing approaches have exploited the chemical reactivity of the OP CWAs, whereas more recently supramolecular‐based approaches using non‐covalent interactions have gained momentum. This is due, in part, to the potential development of sensors with second‐generation properties, such as reversibility and multifunction capabilities. Supramolecular sensors also offer opportunities for incorporation of metal ions allowing for the exploitation of their unique properties. In particular, trivalent lanthanide ions are being increasingly used in the OP CWA sensing event and their use in supramolecular sensors is discussed in this Minireview. We focus on the fundamental interactions of simple lanthanide systems with OP CWAs and simulants, along with the development of more elaborate and complex systems including those containing nanotubes, polymers and gold nanoparticles. Whilst literature investigations into lanthanide‐based OP CWA detection systems are relatively scarce, their unique and versatile properties provide a promising platform for the development of more efficient and complex sensing systems into the future.     

Rhodium(II) Metallopeptide Catalyst Design Enables Fine Control in Selective Functionalization of Natural SH3 Domains

Chemically modified proteins are increasingly important for use in fundamental biophysical studies, chemical biology, therapeutic protein development, and biomaterials. However, chemical methods typically produce heterogeneous labeling and cannot approach the exquisite selectivity of enzymatic reactions. While bioengineered methods are sometimes an option, selective reactions of natural proteins remain an unsolved problem. Here we show that rhodium(II) metallopeptides combine molecular recognition with promiscuous catalytic activity to allow covalent decoration of natural SH3 domains, depending on choice of catalyst but independent of the specific residue present. A metallopeptide catalyst succeeds in modifying a single SH3‐containing kinase at endogenous concentrations in prostate cancer (PC‐3) cell lysate.     

Arylfluorosulfate‐Based Electrophiles for Covalent Protein Labeling: A New Addition to the Arsenal

Selective covalent modification of a targeted protein is a powerful tool in chemical biology and drug discovery, with applications ranging from identification and characterization of proteins and their functions to the development of targeted covalent inhibitors. Most covalent ligands contain an affinity motif and an electrophilic warhead that reacts with a nucleophilic residue of the targeted protein. Because the electrophilic warhead is prone to react and modify off‐target nucleophiles, its reactivity should be balanced carefully to maximize target selectivity. Arylfluorosulfates have recently emerged as latent electrophiles for selective labeling of context‐specific tyrosine and lysine residues in protein pockets. Here, we review the recent but intense introduction of arylfluorosulfates into the arsenal of available warheads for selective covalent modification of proteins. We highlight the untapped potential of this functional group for use in chemical biology and drug discovery.