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1.
Cell ; 185(8): 1431-1443.e16, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35427499

RESUMO

Synthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the autonomous control of therapeutic cells. We examined the function of key domains involved in regulated intramembrane proteolysis and showed that systematic modular engineering can generate a class of receptors that we call synthetic intramembrane proteolysis receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. We demonstrate the therapeutic potential of the receptor platform by engineering human primary T cells for multi-antigen recognition and production of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of fully humanized and customizable transcriptional receptors for the programming of therapeutic cells suitable for clinical translation.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Receptores Artificiais , Humanos , Receptores de Antígenos de Linfócitos T/genética , Receptores Artificiais/genética , Biologia Sintética , Linfócitos T
2.
ChemistryOpen ; 11(4): e202200028, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35373466

RESUMO

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.


Assuntos
Receptores Artificiais , Água , Interações Hidrofóbicas e Hidrofílicas , Receptores Artificiais/química , Solventes/química , Água/química
3.
Langmuir ; 38(7): 2354-2362, 2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35143209

RESUMO

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.


Assuntos
Vírus da Influenza A , Receptores Artificiais , DNA/genética , DNA/metabolismo , Lipídeos , Fusão de Membrana , Receptores Artificiais/metabolismo , Internalização do Vírus
4.
Cell Death Dis ; 13(2): 114, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35121743

RESUMO

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.


Assuntos
Neoplasias Pancreáticas , Receptores Artificiais , Adiponectina/metabolismo , Adiponectina/farmacologia , Ácidos Graxos , Glicólise , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Piperidinas , Receptores de Adiponectina/metabolismo , Receptores Artificiais/metabolismo
5.
Eur J Med Chem ; 231: 114154, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35124532

RESUMO

Large numbers of diverse biologically active molecules are produced from phospholipids, the constituents of biological membranes. Indeed, many lipid-derived ligands, which can undergo inter-transformation between one and another by certain kinases or enzymes, bind to protein receptors such as G-protein-coupled receptors, and serve to regulate multiple biological processes through a variety of signaling pathways. Thus, lipid mediators are likely involved in a synergistic regulatory network, and dysfunction of this network may result in diseases. Here, we reviewed recent progress in the drug development targeting related receptors, focusing on the identification of common structural features which can both come from endogenous ligands or artificial ligands. We also discussed how these features have been utilized in drug design and relevant issues such as potency, selectivity, metabolic stability, and toxicity.


Assuntos
Receptores Artificiais , Ligantes , Lipídeos , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais
6.
Nat Chem Biol ; 18(3): 244-255, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35058646

RESUMO

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).


Assuntos
Receptores Artificiais , Animais , Mamíferos , Biologia Sintética
7.
Mater Horiz ; 9(3): 934-941, 2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35037009

RESUMO

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 via strong and multipoint host-guest interactions between the artificial receptors (cucurbit[7]uril) on the macrophage and the guest ligands (adamantane) selectively anchored on Escherichia coli (E. coli). As a result, the SAR-Macrophage could significantly accelerate the recognition of E. coli, catch and internalize more pathogens, which subsequently induced the M1 polarization of macrophages to generate ROS and effectively kill the intracellular bacteria. Therefore, the SAR-Macrophage represents a simple, yet powerful anti-bacterial approach.


Assuntos
Escherichia coli , Interações entre Hospedeiro e Microrganismos/imunologia , Macrófagos , Receptores Artificiais , Escherichia coli/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Fagocitose
8.
Curr Opin Immunol ; 74: 9-17, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34571290

RESUMO

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.


Assuntos
Neoplasias , Receptores Artificiais , Antígenos/metabolismo , Humanos , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores Artificiais/metabolismo , Linfócitos T
9.
Adv Sci (Weinh) ; 9(4): e2103484, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34837480

RESUMO

A biological receptor serves as sensory transduction from an external stimulus to an electrical signal. It allows humans to better match the environment by filtering out repetitive innocuous information and recognize potentially damaging stimuli through key features, including adaptive and maladaptive behaviors. Herein, for the first time, the authors develop substantial artificial receptors involving both adaptive and maladaptive behaviors using diffusive memristor. Metal-oxide nanorods (NR) as a switching matrix enable the electromigration of an active metal along the surface of the NRs under electrical stimulation, resulting in unique surface-dominated switching dynamics with the advantage of fast Ag migration and fine controllability of the conductive filament. To experimentally demonstrate its potential application, a thermoreceptor system is constructed using memristive artificial receptors. The proposed surface-dominated diffusive memristor allows the direct emulation of the biological receptors, which represents an advance in the bioinspired technology adopted in creating artificial intelligence systems.


Assuntos
Condutividade Elétrica , Nanotecnologia/métodos , Redes Neurais de Computação , Receptores Artificiais , Células Receptoras Sensoriais/fisiologia , Estimulação Elétrica , Desenho de Equipamento , Metais , Óxidos
10.
Molecules ; 26(22)2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34834011

RESUMO

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.


Assuntos
Técnicas Biossensoriais , Análise de Alimentos , Simulação de Dinâmica Molecular , Receptores Artificiais/química , Prata/análise
11.
J Am Chem Soc ; 143(47): 19809-19815, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34793165

RESUMO

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 1H 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.


Assuntos
Calixarenos/química , Complexos de Coordenação/química , Nitrosaminas/análise , Polímeros/química , Receptores Artificiais/química , Calixarenos/síntese química , Complexos de Coordenação/síntese química , Limite de Detecção , Polímeros/síntese química , Técnicas de Microbalança de Cristal de Quartzo , Receptores Artificiais/síntese química , Tungstênio/química
12.
Anal Chim Acta ; 1188: 339177, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34794582

RESUMO

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.


Assuntos
Escherichia coli K12 , Impressão Molecular , Receptores Artificiais , Polímeros Molecularmente Impressos , Shewanella
13.
Biosens Bioelectron ; 194: 113582, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34461567

RESUMO

In the study, we have developed an efficient and robust method using dual modes of fluorescence sensing and smartphone readout for the detection of pyrethroids using artificial receptors inside a covalent organic framework. Carbazole-conjugated frameworks (CCFs) were used to prepare efficient fluorescent probes that combine stability with light-emitting activity. CN linkages between aldehydes and amines formed Schiff bases, allowing the development of layered structures, creating exceptionally stable frameworks. Artificial receptors that can bind compounds inside the CCFs with high affinity, for both the detection and absorption of λ-cyhalothrin (LC), were constructed using room-temperature reverse microemulsion polymerization. Under optimum conditions, the fluorescence sensing correlation with the concentration of LC showed good linearity in the range of 0.8-175 µg L-1 with a detection limit of 0.368 µg L-1. The smartphone-based visible readout exhibited a good effect, with a detection limit of 4.067 µg L-1, and recovery of 88 %-103% in food samples. A parallel analysis in food samples was conducted by high-performance liquid chromatography, the results showed good consistency, indicating the practicability of the developed method. Dual mode analysis can avoid the disadvantages of a single response, providing excellent sensitivity, specificity, and efficiency through a strong binding force between the target and the artificial receptors.


Assuntos
Técnicas Biossensoriais , Estruturas Metalorgânicas , Piretrinas , Receptores Artificiais , Smartphone
14.
Methods Mol Biol ; 2312: 15-33, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34228282

RESUMO

Synthetic receptors control cell behavior in response to environmental stimuli for applications in basic research and cell therapy. However, the integration of synthetic receptors in unexplored contexts is cumbersome, especially for nonspecialist laboratories. Here, I provide a detailed protocol on how to use receptors of the generalized extracellular molecule sensor (GEMS) platform. GEMS is a modular receptor system that can be adapted to sense molecules of choice by using affinity domains that dimerize in response to the target. GEMS consist of an erythropoietin receptor scaffold that has been mutated to no longer bind to erythropoietin. N-terminal fusions with affinity domains, such as single chain variable fragments (scFvs), that bind to two epitopes on the same target activate the receptor. The intracellular receptor domain can be chosen from several signal transduction domains of single-pass transmembrane receptors to activate endogenous signaling pathways. As of now, GEMS have been used for sensing prostate specific antigen (PSA), the synthetic azo dye RR120, caffeine, nicotine, rapamycin, the SunTag peptide, and a de novo designed protein displaying two viral epitopes. The tested intracellular domains were derived from FGFR1, IL-6RB, and VEGFR2, and were used to drive transgene expression from reporter plasmids responsive to the endogenous transcription factors STAT3, NFAT, NF-κB, and a synthetic transcription factor activated by the MAPK pathway. In this protocol, I focus on transient transfections of HEK293T cells and include several general notes about cell handling. While the described methods are optimized for experiments with GEMS, most of the described techniques are general procedures to set up synthetic biology experiments in mammalian cell culture. I outline how to generate stable cell lines and share tips on how to adapt GEMS for new ligands. The main objective of this protocol is to make the GEMS technology accessible also to nonspecialist laboratories to facilitate the use of synthetic receptors in new research contexts.


Assuntos
Técnicas Biossensoriais , Engenharia Celular , Engenharia de Proteínas , Receptores Artificiais/genética , Receptores da Eritropoetina/genética , Anticorpos de Cadeia Única/genética , Biologia Sintética , Afinidade de Anticorpos , Receptor gp130 de Citocina/genética , Epitopos , Genes Reporter , Células HEK293 , Humanos , Ligantes , Mutação , Domínios e Motivos de Interação entre Proteínas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptores Artificiais/metabolismo , Receptores da Eritropoetina/metabolismo , Transdução de Sinais , Anticorpos de Cadeia Única/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
15.
Biochem Biophys Res Commun ; 566: 148-154, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34126345

RESUMO

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.


Assuntos
Receptores Artificiais/química , Tirosina/química , Animais , Linhagem Celular , Camundongos , Multimerização Proteica , Transdução de Sinais , Biologia Sintética , Proteínas de Ligação a Tacrolimo/química
16.
Biosensors (Basel) ; 11(2)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670184

RESUMO

Foodborne illnesses represent high costs worldwide in terms of medical care and productivity. To ensure safety along the food chain, technologies that help to monitor and improve food preservation have emerged in a multidisciplinary context. These technologies focus on the detection and/or removal of either biological (e.g., bacteria, virus, etc.) or chemical (e.g., drugs and pesticides) safety hazards. Imprinted polymers are synthetic receptors able of recognizing both chemical and biological contaminants. While numerous reviews have focused on the use of these robust materials in extraction and separation applications, little bibliography summarizes the research that has been performed on their coupling to sensing platforms for food safety. The aim of this work is therefore to fill this gap and highlight the multidisciplinary aspects involved in the application of imprinting technology in the whole value chain ranging from IP preparation to integrated sensor systems for the specific recognition and quantification of chemical and microbiological contaminants in food samples.


Assuntos
Impressão Molecular , Polímeros , Inocuidade dos Alimentos , Praguicidas , Receptores Artificiais
17.
AAPS PharmSciTech ; 22(3): 93, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33683499

RESUMO

Heterogeneity in tumor expression as well as expression in normal tissues of various targets limit the usefulness of current ligand-based active targeting approaches. Incorporation of synthetic receptors, which can be recognized by delivery systems engineered to present specific functional groups on the surface, is a novel approach to improve tumor targeting. Alternatively, introduction of synthetic functionalities on cellular carriers can also enhance tumor targeting. We review various strategies that have been utilized for the introduction of synthetic targets in tumor tissues. The introduction of synthetic functional groups in the tumor through improved strategies is anticipated to result in improved target specificity and reduced heterogeneity in target expression.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Receptores Artificiais , Receptores de Droga/efeitos dos fármacos , Animais , Portadores de Fármacos , Humanos , Nanotecnologia
18.
ACS Appl Mater Interfaces ; 13(12): 14004-14014, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33728894

RESUMO

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.


Assuntos
Membrana Celular/metabolismo , Ciclo-Octanos/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Animais , Linhagem Celular Tumoral , Clorofilídeos , Ciclo-Octanos/farmacocinética , Ciclo-Octanos/uso terapêutico , Humanos , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/uso terapêutico , Neoplasias/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacocinética , Porfirinas/uso terapêutico , Receptores Artificiais/metabolismo
19.
Science ; 371(6534): 1166-1171, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33632893

RESUMO

Overexpressed tumor-associated antigens [for example, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)] are attractive targets for therapeutic T cells, but toxic "off-tumor" cross-reaction with normal tissues that express low levels of target antigen can occur with chimeric antigen receptor (CAR)-T cells. Inspired by natural ultrasensitive response circuits, we engineered a two-step positive-feedback circuit that allows human cytotoxic T cells to discriminate targets on the basis of a sigmoidal antigen-density threshold. In this circuit, a low-affinity synthetic Notch receptor for HER2 controls the expression of a high-affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells-it increases both CAR expression and activation-leading to a sigmoidal response. T cells with this circuit show sharp discrimination between target cells expressing normal amounts of HER2 and cancer cells expressing 100 times as much HER2, both in vitro and in vivo.


Assuntos
Engenharia Celular , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Humanos , Imunoterapia Adotiva , Células K562 , Camundongos , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Receptores Artificiais/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Esferoides Celulares , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Chem Rev ; 121(4): 2445-2514, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33472000

RESUMO

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.


Assuntos
Compostos Macrocíclicos/química , Receptores Artificiais/química , Água/química , Eletricidade Estática , Termodinâmica
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