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The development of artificial receptors for efficient recognition of analytes in water is a challenging task. Homooxacalix[3]arene-based receptor

Influenza A virus (IAV) binds to sialylated glycans on the cell membrane before endocytosis and fusion. Cell-surface glycans are highly heterogeneous in length and glycosylation density, which leads to variations in the distance and rigidity with which IAV is held away from the cell membrane. To gain mechanistic insight into how receptor length and rigidity impact the mechanism of IAV entry, we employed synthetic DNA–lipids as highly tunable surrogate receptors. We tethered IAV to target membranes with a panel of DNA–lipids to investigate the effects of the distance and tether flexibility between virions and target membranes on the kinetics of IAV binding and fusion. Tether length and the presence of a flexible linker led to higher rates of IAV binding, while the efficiencies of lipid and content mixing were typically lower for longer and more rigid DNA tethers. For all DNA tether modifications, we found that the rates of IAV lipid and content mixing were unchanged. These results suggest that variations in the interface between IAV and a target membrane do not significantly impact the rate-limiting step of fusion or the low-pH-triggered engagement of viral fusion peptides with the target membrane. However, our results imply that the flexibility of the viral receptor is important for ensuring that hemifusion events are able to successfully proceed to pore formation.

Obesity creates a localized inflammatory reaction in the adipose, altering secretion of adipocyte-derived factors that contribute to pathologies including cancer. We have previously shown that adiponectin inhibits pancreatic cancer by antagonizing leptin-induced STAT3 activation. Yet, the effects of adiponectin on pancreatic cancer cell metabolism have not been addressed. In these studies, we have uncovered a novel metabolic function for the synthetic adiponectin-receptor agonist, AdipoRon. Treatment of PDAC cells with AdipoRon led to mitochondrial uncoupling and loss of ATP production. Concomitantly, AdipoRon-treated cells increased glucose uptake and utilization. This metabolic switch further correlated with AMPK mediated inhibition of the prolipogenic factor acetyl coenzyme A carboxylase 1 (ACC1), which is known to initiate fatty acid catabolism. Yet, measurements of fatty acid oxidation failed to detect any alteration in response to AdipoRon treatment, suggesting a deficiency for compensation. Additional disruption of glycolytic dependence, using either a glycolysis inhibitor or low-glucose conditions, demonstrated an impairment of growth and survival of all pancreatic cancer cell lines tested. Collectively, these studies provide evidence that pancreatic cancer cells utilize metabolic plasticity to upregulate glycolysis in order to adapt to suppression of oxidative phosphorylation in the presence of AdipoRon.

Receptors enable cells to detect, process and respond to information about their environments. Over the past two decades, synthetic biologists have repurposed physical parts and concepts from natural receptors to engineer synthetic receptors. These technologies implement customized sense-and-respond programs that link a cell's interaction with extracellular and intracellular cues to user-defined responses. When combined with tools for information processing, these advances enable programming of sophisticated customized functions. In recent years, the library of synthetic receptors and their capabilities has substantially evolved-a term we employ here to mean systematic improvement and expansion. Here, we survey the existing mammalian synthetic biology toolkit of protein-based receptors and signal-processing components, highlighting efforts to evolve and integrate some of the foundational synthetic receptor systems. We then propose a generalized strategy for engineering and improving receptor systems to meet defined functional objectives called a 'metric-enabled approach for synthetic receptor engineering' (MEASRE).

N-Nitrosamines are found in food, drugs, air, water, and soil. They pose a significant risk to human health because of their carcinogenicity; consequently, materials that can be used to selectively and sensitively detect nitrosamines are needed. In this work, we designed and synthesized two polymers bearing calix[4]arene or 4-tert-butylcalix[4]arene tungsten−imido complexes (PCalixH and PCalixtBu) as N-nitrosodimethylamine (NDMA) receptors. The interaction between metallocalix[4]arene monomers/polymers and NDMA was confirmed by (1)H NMR and IR spectroscopy. Single-crystal X-ray analysis further revealed that the host−guest interaction is based on binding of the terminal oxygen of NDMA to tungsten within the calixarene cavity. Gravimetric detection of NDMA was performed on a quartz crystal microbalance (QCM) in air. Both polymers show responses to NDMA, with PCalixtBu exhibiting a low theoretical limit of detection of 5 ppb for NDMA. The sensor also shows high selectivity toward NDMA and moderate humidity tolerance. This work provides a sensitive sensor for detection of NDMA and also offers a class of new, selective, and efficient NDMA receptors for the future design of NDMA sensors and NDMA extraction materials.

A flexible electrochemical sensor based on the carbon felt (CF) functionalized with Bisphenol A (BPA) synthetic receptors was developed. The artificial Bisphenol A receptors were grafted on the CF by a simple thermal polymerization molecular imprinting process. Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and electrochemical characterizations were used to analyze the receptors. Characterization results demonstrated that the Bisphenol A synthetic receptors successfully formed on the CFs surface. Because the synthetic receptor and the porous CFs were successfully combined, the sensor displayed a better current response once Bisphenol A was identified. The sensor’s linear range was determined to be from 0.5 to 8.0 nM and 10.0 to 300.0 nM, with a detection limit of 0.36 nM. Even after being bent and stretched repeatedly, the electrode’s performance was unaffected, demonstrating the robustness, adaptability and viability of installing the sensor on flat or curved surfaces for on-site detection. The designed electrochemical sensor has been used successfully to identify Bisphenol A in milk samples with satisfactory results. This work provided a promising platform for the design of implantable, portable and miniaturized sensors.

As intracellular signal transduction is important for determining cell fate, artificial control of signaling properties through engineered receptors is attractive in the fields of synthetic biology and cell therapy. In this study, we tailored minimal synthetic receptors to reconstitute signaling properties by incorporating multiple tyrosine motifs. The size of molecular parts including the linker between the tyrosine motifs was minimized as much as possible to create the minimal synthetic receptors. By combining the membrane localization signal sequence, a mutant of FK506-binding protein, a JAK-binding domain, tyrosine motifs, and linkers, we successfully reconstituted simple receptor chains that were activated by dimerization via a synthetic small-molecule ligand capable of membrane permeation. Furthermore, up to four signaling molecules of interest were able to be recruited and activated by the minimal synthetic receptors. Thus, the tailored minimal synthetic receptors could be utilized to analyze the role of specific signaling molecules/pathways in controlling cell fate and to efficiently induce specific cell fate for therapeutic applications in the future.

Abnormal productions of amyloid beta (Aβ) plaque and chronic neuroinflammation are commonly observed in the brain of patients with Alzheimer’s disease, and both of which induce neuronal cell death, loss of memory, and cognitive dysfunction. However, many of the drugs targeting the production of Aβ peptides have been unsuccessful in treating Alzheimer’s disease. In this study, we identified synthetic novel peroxisome proliferator-activating receptor (PPAR) agonist, DTMB, which can ameliorate the chronic inflammation and Aβ pathological progression of Alzheimer’s disease. We discovered that DTMB attenuated the proinflammatory cytokine production of microglia by reducing the protein level of NF-κB. DTMB also improved the learning and memory defects and reduced the amount of Aβ plaque in the brain of 5xFAD mice. This reduction in Aβ pathology was attributed to the changes in gliosis and chronic inflammation level. Additionally, bulk RNA-sequencing showed that genes related to inflammation and cognitive function were changed in the hippocampus and cortex of DTMB-treated mice. Our findings demonstrate that DTMB has the potential to be a novel therapeutic agent for Alzheimer’s disease. Graphical abstract

Developing novel activatable photosensitizers with excellent plasma membrane targeting ability is urgently needed for smart photodynamic therapy (PDT). Herein, a tumor acidity-activatable photosensitizer combined with a two-step bioorthogonal pretargeting strategy to anchor photosensitizers on the plasma membrane for effective PDT is developed. Briefly, artificial receptors are first anchored on the cell plasma membrane using cell-labeling agents (Az-NPs) via the enhanced permeability and retention effect to achieve the tumor cell labeling. Then, pH-sensitive nanoparticles (S-NPs) modified with dibenzocyclooctyne (DBCO) and chlorin e6 (Ce6) accumulate in tumor tissue and disassemble upon protonation of their tertiary amines in response to the acidic tumor environment, exposing the contained DBCO and Ce6. The selective, highly specific click reactions between DBCO and azide groups enable Ce6 to be anchored on the tumor cell surface. Upon laser irradiation, the cell membrane is severely damaged by the cytotoxic reactive oxygen species, resulting in remarkable cellular apoptosis. Taken together, the membrane-localized PDT by our bioorthogonal pretargeting strategy to anchor activatable photosensitizers on the plasma membrane provides a simple but effective method for enhancing the therapeutic efficacy of photosensitizers in anticancer therapy.

Molecular recognition in water using macrocyclic synthetic receptors constitutes a vibrant and timely research area of supramolecular chemistry. Pioneering examples on the topic date back to the 1980s. The investigated model systems and the results derived from them are key for furthering our understanding of the remarkable properties exhibited by proteins: high binding affinity, superior binding selectivity, and extreme catalytic performance. Dissecting the different effects contributing to the proteins' properties is severely limited owing to its complex nature. Molecular recognition in water is also involved in other appreciated areas such as self-assembly, drug discovery, and supramolecular catalysis. The development of all these research areas entails a deep understanding of the molecular recognition events occurring in aqueous media. In this review, we cover the past three decades of molecular recognition studies of neutral and charged, polar and nonpolar organic substrates and ions using selected artificial receptors soluble in water. We briefly discuss the intermolecular forces involved in the reversible binding of the substrates, as well as the hydrophobic and Hofmeister effects operating in aqueous solution. We examine, from an interdisciplinary perspective, the design and development of effective water-soluble synthetic receptors based on cyclic, oligo-cyclic, and concave-shaped architectures. We also include selected examples of self-assembled water-soluble synthetic receptors. The catalytic performance of some of the presented receptors is also described. The latter process also deals with molecular recognition and energetic stabilization, but instead of binding ground-state species, the targets become elusive counterparts: transition states and other high-energy intermediates.

Ubiquitination is a prevalent post-translational modification that controls a multitude of important biological processes. Due to the low abundance of ubiquitinated proteins, highly efficient separation and enrichment approaches are required for ubiquitinome analysis. In this work, we disclose the region-specific interactions between the hydrophobic patch of ubiquitin and polydopamine. Taking advantage of this inherent binding property, we have constructed surface-imprinted magnetic nanoparticles (NPs) for ubiquitin by sequential dopamine polymerization and surface PEGylation. The obtained molecularly imprinted polymer (MIP) NPs showed a binding constant of 2.6 × 10

Molecular recognition processes in water differ from those in organic solvents in that they are mediated to a much greater extent by solvent effects. The hydrophobic effect, for example, causes molecules that only weakly interact in organic solvents to stay together in water. Such water-mediated interactions can be very efficient as demonstrated by many of the synthetic receptors discussed in this review, some of which have substrate affinities matching or even surpassing those of natural binders. However, in spite of considerable success in designing such receptors, not all factors determining their binding properties in water are fully understood. Existing concepts still provide plausible explanations why the reorganization of water molecules often causes receptor-substrate interactions in water to be strongly exothermic rather than entropically favored as predicted by the classical view of the hydrophobic effect.

Feeling temperature and touch The range of receptors in our skin make it possible to sense when we are touching an object and also gives us a general sense of the temperature of that object. Achieving this in an artificial skin-like material has been a challenge because most of the approaches for sensing touch are themselves temperature sensitive. You et al. studied the ion relaxation dynamics in a conductive elastomeric film (see the Perspective by Liu). They show that the ion relaxation time can be used as a strain-insensitive intrinsic variable for detecting temperature and the capacitance can be used as a temperature-insensitive extrinsic variable for sensing the strain, thus decoupling the two so that their signals do not interfere with each other. Science , this issue p. 961 ; see also p. 910

Carbohydrate-receptor interactions are often involved in the docking of viruses to host cells, and this docking is a necessary step in the virus life cycle that precedes infection and, ultimately, replication. Despite the conserved structures of the glycans involved in docking, they are still considered "undruggable", meaning these glycans are beyond the scope of conventional pharmacological strategies. Recent advances in the development of synthetic carbohydrate receptors (SCRs), small molecules that bind carbohydrates, could bring carbohydrate-receptor interactions within the purview of druggable targets. Here we discuss the role of carbohydrate-receptor interactions in viral infection, the evolution of SCRs, and recent results demonstrating their ability to prevent viral infections in vitro. Common SCR design strategies based on boronic ester formation, metal chelation, and noncovalent interactions are discussed. The benefits of incorporating the idiosyncrasies of natural glycan-binding proteins-including flexibility, cooperativity, and multivalency-into SCR design to achieve nonglucosidic specificity are shown. These studies into SCR design and binding could lead to new strategies for mitigating the grave threat to human health posed by enveloped viruses, which are heavily glycosylated viroids that are the cause of some of the most pressing and untreatable diseases, including HIV, Dengue, Zika, influenza, and SARS-CoV-2.

Xyloglucan is a mucoadhesive polysaccharide which is extracted from the cell wall of vascular plants. Tamarind seeds are the abundant source of xyloglucan and commercially more popular. It is biocompatible, biodegradable, and nontoxic in nature. It is approved by the FDA for use as a food additive, stabilizing and thickening agent or gelling agent. Recently, many researchers are giving attention to xyloglucan for drug delivery through various routes and regeneration of the number of tissues. However, the findings of tissue regeneration and drug delivery in combination are not collected and represented in a simple and comprehensive way. The aim of this review is to find and represent these missing links. This review presents current researches on xyloglucan in drug delivery and regeneration of tissue.

A novel and facile fluorescent artificial receptor on the basis of the molecularly imprinted polymer-coated graphene quantum dots was engineered successfully to detect colistin. The colistin imprinted graphene quantum dots (CMIP-GQDs) was synthesized by vinyl-based radical polymerization between functional monomers and crosslinker at around the template molecule on the surface of graphene quantum dots. The size of bare, CNIP-GQDs, and CMIP-GQDs was about 4.8 +/- 0.6 nm, 18.4 +/- 1.7 nm, and 19.7 +/- 1.3 nm, respectively. The CMIP-GQDs, which showed the strong fluorescence emission at 440 nm with the excitation wavelength fixed at 380 nm, had excellent selectivity and specificity to rapidly recognize and detect colistin. The linear range of fluorescence quenching of this fluorescent artificial receptor for detection colistin was 0.016-2.0 mu g mL(-1) with a correlation coefficient (R-2) of 0.99919, and the detection limit was 7.3 ng mL(-1) in human serum samples. The designed receptor was successfully applied to detect colistin in human serum samples and it achieved excellent recoveries shifted from 93.8 to 105%.

Selective recognition of natural fatty acids is intrinsically difficult owing to the long, flexible, and poorly interactive hydrocarbon chains. Inspired by biological recognition systems, we herein demonstrate the exclusive binding of a monounsaturated fatty acid by an artificial polyaromatic receptor from a mixture of the unsaturated and corresponding saturated substrates (i.e., oleic and stearic acids) in water. The selectivity stems from multiple CH-π/π-π interactions between the host framework and the guest in its roughly coiled conformation. Moreover, competitive binding experiments elucidate higher binding affinities of the receptor for oligo- and polyunsaturated fatty acids (e.g., α-linolenic acid and EPA). Within the receptor, the biosubstrates are remarkably stabilized against air, light, and heat owing to the polyaromatic shielding effect.

Artificial receptor‐based protein assays have various attractive features such as a long‐term stability, a low‐cost production process, and the ease of tuning the target specificity. However, such protein sensors are still immature compared with conventional immunoassays. To enhance the application potential of synthetic sensing materials, organic field‐effect transistors (OFETs) are some of the suitable platforms for protein assays because of their solution processability, durability, and compact integration. Importantly, OFETs enable the electrical readout of the protein recognition phenomena of artificial receptors on sensing electrodes. Thus, we believe that OFETs functionalized with artificial protein receptors will be a powerful tool for the on‐site analyses of target proteins. In this Minireview, we summarize the recent progress of the OFET‐based protein assays including the rational design strategies for devices and sensing materials., OFETs go next: Organic field‐effect transistors (OFETs) functionalized with artificial receptors offer simple methods for the sensitive and selective detection of proteins and their chemical information, such as post‐translational modifications. Thus, the OFETs will be new caididates for the next‐generation electronic devices for healthcare applications.

Notch signaling is highly conserved in most animals and plays critical roles during neurogenesis as well as embryonic development. Synthetic Notch-based systems, modeled from Notch receptors, have been developed to sense and respond to a specific extracellular signal. Recent advancement of synNotch has shown promise for future use in cellular engineering to treat cancers. However, synNotch from Morsut et al. (2016) has a high level of ligand-independent activation, which limits its application. Here we show that adding an intracellular hydrophobic sequence (QHGQLWF, named as RAM7) present in native Notch, significantly reduced ligand-independent activation. Our enhanced synthetic Notch receptor (esNotch) demonstrates up to a 14.6-fold reduction in ligand-independent activation, without affecting its antigen-induced activation efficiency. Our work improves a previously reported transmembrane receptor and provides a powerful tool to develop better transmembrane signaling transduction modules for further advancement of eukaryotic synthetic biology., Zi-jie Yang et al. show that adding a hydrophobic sequence (QHGQLWF) present in endogenous Notch reduces ligand-independent activation of the existing synthetic Notch receptor by 15 folds. This enhanced synthetic Notch receptor maintains its antigen-induced activation efficiency, demonstrating its utility for synthetic biology.

Carbohydrates are important but challenging targets for supramolecular chemists. They possess complex, irregular and variable structures, and are strongly attracted to water, their natural environment. This tutorial review describes work on synthetic receptors which bind carbohydrates through non-covalent interactions, mimicking the strategies used in biology. Emphasis is placed on systems which operate in purely aqueous solution, without involvement of organic solvents. Although the problem is difficult, the careful design of complementary cavities can lead to surprisingly good results. In particular, a receptor for glucose has achieved performance which generally matches biology, and augurs well for real-world applications.

Bacterial infection has become a global concern owing to the significant morbidity and mortality. Although the phagocytosis of bacteria by immune cells acts as the front line to protect human body from invading pathogens, the relatively slow encounter and insufficient capture of bacteria by immune cells often lead to an inefficient clearance of pathogens. Herein, a supramolecular artificial receptor-modified macrophage (SAR-Macrophage) was developed to enhance the recognition and latch of bacteria in the systemic circulation, mediated

Work on the use of cyclic peptides or pseudopeptides as synthetic receptors started even before the field of supramolecular chemistry was firmly established. Research initially focused on the development of synthetic ionophores and involved the use of macrocycles with a repeating sequence of subunits along the ring to facilitate the correlation between structure, conformation, and binding properties. Later, nonnatural amino acids as building blocks were also considered. With growing research in this area, cyclopeptides and related macrocycles developed into an important and structurally diverse receptor family. This review provides an overview of these developments, starting from the early years. The presented systems are classified according to characteristic structural elements present along the ring. Wherever possible, structural aspects are correlated with binding properties to illustrate how natural or nonnatural amino acids affect binding properties.

Synthetic receptors targeted to the secretory pathway often fail to exhibit the expected activity due to post-translational modifications (PTMs) and/or improper folding. Here, we engineered synthetic receptors that reside in the cytoplasm, inside the endoplasmic reticulum (ER), or on the plasma membrane through orientation adjustment of the receptor parts and by elimination of dysfunctional PTMs sites. The cytoplasmic receptors consist of split-TEVp domains that reconstitute an active protease through chemically-induced dimerization (CID) that is triggered by rapamycin, abscisic acid, or gibberellin. Inside the ER, however, some of these receptors were non-functional, but their activity was restored by mutagenesis of cysteine and asparagine, residues that are typically associated with PTMs. Finally, we engineered orthogonal chemically activated cell-surface receptors (OCARs) consisting of the Notch1 transmembrane domain fused to cytoplasmic tTA and extracellular CID domains. Mutagenesis of cysteine residues in CID domains afforded functional OCARs which enabled fine-tuning of orthogonal signalling in mammalian cells., Nature Communications, 13 (1), ISSN:2041-1723

The linkage of two identical binding motifs by a molecular photoswitch has proven to be a straightforward and versatile strategy to control substrate binding affinity by light. Stimulus control of binding properties in artificial receptors is partly inspired by the dynamic behavior of proteins and is highly attractive as it could, for example, improve extraction processes and allow (de)activation of membrane transport on demand. This feature article summarizes the development and design principles of molecular tweezers containing a molecular photoswitch as the core unit. Besides the control of binding affinity by isomerization, the effect of substrate binding on the isomerization behavior is discussed where data is available. While the latter often receives less attention, it could be of benefit in the future creation of multi-stimuli-controlled molecular switching and machine-like systems.

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.

International audience; We fabricated an electrochemical molecularly imprinted polymer (MIP) chemosensor for rapid identification and quantification of E. coli strain using 2-aminophenyl boronic acid as the functional monomer. This strain is a modified Gram-negative strain of Escherichia coli bacterium, an ordinary human gut component. The E. coli strongly interacts with a boronic acid because of porous and flexible polymers of the cell wall. The SEM imaging showed that the bacteria template was partially entrapped within the polymeric matrix in a single step. Moreover, this imaging confirmed E. coli K-12 cell template extraction effectiveness. The prepared MIP determined the E. coli K-12 strain up to 2.9 × 104 cells mL−1. The interference study performed in the presence of E. coli variants expressing different surface appendages (type 1 fimbriae or Antigen 43 protein) or Shewanella oneidensis MR1, another Gram-negative bacteria, demonstrated that the bacterial surface composition notably impacts sensing properties of the bacteria imprinted polymer.

Adoptive cell therapy with T cells engineered with customized receptors that redirect antigen specificity to cancer cells has emerged as an effective therapeutic approach for many malignancies. Toxicity due to on target or off target effects, antigen heterogeneity on cancer cells, and acquired T cell dysfunction have been identified as barriers that can hinder successful therapy. This review will discuss recent advances in T cell engineering that have enabled the application of logic gates in T cells that can mimic the integration of natural signaling pathways and act in a cell intrinsic or extrinsic fashion to precisely target tumor cells and regulate effector functions, potentially overcoming these barriers to effective therapy.

Chiral cholesteric molecular tweezer 7a was synthesized, and its recognition properties for Ag+, Al3+, Ca2+ etc., were investigated by UV and fluorescence spectra. The results showed that in ethanol/Tris (1/1, v/v, pH 7.0) buffer solution, the host molecular tweezer 7a had a specific recognition ability for Ag+, the detection limit was up to 1 × 10−6 mol/L, and other metal ions had little effect on Ag+ recognition. At the same time, the naked-eye detection of Ag+ was realized by the light red color of the complex solution. Furthermore, the mechanism of recognition of Ag+ by molecular tweezer 7a was studied by a nuclear magnetic titration test and computer molecular simulation, and a rapid detection method of Ag+ using host molecular tweezer 7a was established. Through the determination of Ag+ in milk powder, quinoa and other food samples, it was proved that this novel method had a good application prospect for the detection of Ag+ in food.