Accounts of Chemical Research最新文献

{"title":"Targeting Fibroblast Activation Protein for Precision Medicine","authors":"Jie Liu, Xinzhi Zhao, Peifei Liu, Jinming Yu, Xiaoyuan Chen, Jingjing Zhang","doi":"10.1021/acs.accounts.6c00139","DOIUrl":"10.1021/acs.accounts.6c00139","url":null,"abstract":"<p>The advancement of precisionmedicine dependscritically on well-definedmolecular targets. Pathologically activated fibroblasts drive diseaseprogression in cancer, fibrosis and chronic inflammation through sustainedinflammation, extracellular matrix remodeling and pathological microenvironmentformation. Among available markers, fibroblast activation protein(FAP) stands out due to its selective overexpression in diseased tissuesversus minimal expression in healthy organs. This unique profile makesFAP a promising target for molecular imaging and targeted therapy,enabling precision theranostics across both oncological and nononcologicaldiseases.</p><p>FAP-targeted theranostics originated from the leadcompound PT-100,which established the core pharmacophore. Subsequent key advance wasthe replacement of the boronic acid warhead with a cyano group, alongwith the introduction of fluorine and quinoline moieties, yieldingthe UAMC-1110 scaffold. This scaffold exhibits improved bioactivityand favorable pharmacokinetics. Systematic modification of the quinolineside chain and conjugation with chelators have allowed efficient radiolabeling,positioning radiolabeled FAP inhibitors as promising tools for precisiontheranostics. However, continued optimization of UAMC-1110-derivedprobes to enhance their stability, affinity, tumor retention, andcellular uptake, together with integration into advanced strategiessuch as nanomedicine, remains essential not only for refining FAP-targetedprecision medicine but also for expanding its applications beyondoncology to nononcological diseases.</p><p>Unlike previous reviews,this Account organizes the field arounda unified chemical design language, following a “rational design-pharmacokinetics-translationalvalidation” paradigm. After delineating the core biologicalfunctions of FAP-expressing fibroblasts in disease pathogenesis, wesystematically examine the rapid advancement of radionuclide-labeledFAPIs, including optimization of linkers, chelators, and albumin-bindingmoieties, along with multimerization strategies, which significantlyenhanced the pharmacokinetic profiles. Key innovations in the fieldinclude three strategic approaches. First, the albumin-binding therapeuticagent [<sup>177</sup>Lu]Lu-EB-FAPI achieves prolonged tumor retentionand promising efficacy. Second, multimerization strategies have yieldedbivalent and tetrameric FAPI constructs, which exhibit superior tumoraccumulation. Third, heterodimeric probes such as [<sup>68</sup>Ga]Ga-FAPI-RGDand [<sup>68</sup>Ga]Ga-FAPI-LM3 enable dual targeting of FAP alongwith integrin αvβ3 or somatostatin receptor SSTR2, therebyaddressing tumor heterogeneity and enhancing lesion detectability.Subsequently, the application scope of FAPI-based imaging has beenexpanded from oncology to nononcological diseases. The value of thistechnique in visualizing dynamic remodeling processes across key pathologicconditions has been established, offering quantitative assessmentbeyond the reach o","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 16","pages":"2615–2634"},"PeriodicalIF":18.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148675466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Self-Driving Scanning Probe Microscopy: From Acceleration to Discovery and Manipulation","authors":"Ganesh Narasimha,&nbsp;Ralph Bulanadi,&nbsp;Jawad Chowdhury,&nbsp;Rama Vasudevan,&nbsp;Yongtao Liu","doi":"10.1021/acs.accounts.6c00273","DOIUrl":"10.1021/acs.accounts.6c00273","url":null,"abstract":"<p>Scanning probe microscopy offers a powerful suite of techniquesfor investigating meso-, micro- and nanoscale phenomena ─ enablingthe exploration of advanced materials, heterostructures, quantum materials,as well as providing insight into surface energetics and reactions.Additional spectroscopic capabilities combined with multimodal imagingallow for spatially resolved characterization of functional materialproperties. Despite its central role, microscopy is still predominantlyconducted through a sequential, operator-driven workflow in whichdata acquisition, interpretation, and subsequent experimental decisionsoccur in discrete steps. This approach not only reduces experimentalthroughput but also limits the effective utilization of increasinglycomplex multimodal data sets, where critical information may remainunrecognized across real-time data streams.</p><p>Recent advancesin artificial intelligence (AI) and machine learning(ML) have enabled the concept of self-driving laboratories (SDL) whichpromise to accelerate scientific research by closing the loop betweendata acquisition, analysis, and experimental control. Within thisbroader paradigm, self-driving microscopy (SDM) has emerged as a powerfulapproach to overcome the limitations of traditional, operator-drivenmicroscopy workflows. In this Account, we discuss the evolution ofSDM from automated experimental platforms to fully autonomous systemscapable of adaptive, decision-driven operation. We highlight its implementationfor real-time data processing and optimization, feature identification,and strategies to efficiently explore across multidimensional parameterspaces. Advanced optimization strategies, including Bayesian optimizationand reinforcement learning, allow SDM systems to iteratively refineexperimental parameters based on prior observations, prioritizingmeasurements that maximize information gain. This adaptive approachreduces the total number of experiments required while improving theefficiency of exploration.</p><p>Collectively, we showcase how SDMaccelerates microscopy throughAI/ML integration, enables real-time analysis from high-dimensionaldata acquisition, while simultaneously guiding the experiments towarddiscovery. In addition to characterization, the autonomous workflowsallow for active material manipulation to create nanoscale artificialstructures on demand. We highlight that formalizing experimental strategiesinto algorithmic workflows enhances integration and scalability acrossinstruments and laboratories. These advances position SDM as a broadlyapplicable paradigm at the forefront of next-generation experimentalscience.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 16","pages":"2635–2646"},"PeriodicalIF":18.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Controllable and Diverse Migrations of Tetracoordinate Borons: Beyond 1,2-Shift","authors":"Xingxing Ma,&nbsp;Qiuling Song","doi":"10.1021/acs.accounts.6c00451","DOIUrl":"10.1021/acs.accounts.6c00451","url":null,"abstract":"&lt;p&gt;The chemistry of tetracoordinateborons has long been dominatedby the classic 1,2-metalate shift, a powerful yet inherently predictablerearrangement where the migrating aptitude is dictated by the electronicbias of the substituents. Breaking free from this paradigm to achievecontrollable and diverse migration─beyond 1,2-shift─remainsa formidable challenge. &lt;em&gt;In this Account&lt;/em&gt;, we describeour systematic efforts to unlock three previously inaccessible dimensionsof tetracoordinate boron reactivity: ionic remote migrations, radicalremote migrations, and programmable sequential multiple migrationson a single boron center. Across these three manifolds, the feasibilityof migration is governed by three common factors: migration distanceis constrained by the size of the cyclic transition state (rings of5–7 members are viable); the aptitude of a migrating groupdepends on its ability to stabilize developing charge in ionic pathwaysor radical character in radical pathways; and conformational preorganizationis essential for ionic remote migrations, while radical variants aremore tolerant due to the extended lifetime of the radical intermediate.Distilled from systematic mechanistic studies, these principles establisha predictive framework for the design of new migrations.&lt;/p&gt;&lt;p&gt;Ourjourney began with the realization that the conventional 1,2-shiftis not the only option. By carefully designing the tetracoordinateboron frameworks and the external stimulus, we can direct a substituentto migrate over a longer distance. In the ionic manifold, we developedremote 1,&lt;em&gt;n&lt;/em&gt;-metalate shifts (&lt;em&gt;n&lt;/em&gt; ≥3) in which heteroatoms (hydroxyl, bromine, hydride) and carbon substituentsmigrate over 1,3-, 1,4-, and even 1,7-distances, enabling stereospecificketoxime synthesis, enantioselective construction of axially chiralalkenes, skeletal editing of &lt;em&gt;N&lt;/em&gt;-heterocycles, a Passerini-typemulticomponent reaction, enolate-driven C(&lt;em&gt;sp&lt;/em&gt;&lt;sup&gt;2&lt;/sup&gt;)–C(&lt;em&gt;sp&lt;/em&gt;&lt;sup&gt;3&lt;/sup&gt;) cross-coupling,and asymmetric indole reduction─all with a level of controlunattainable by classical methods. Second, we turned to a completelyorthogonal activation mode: radical-induced remote migrations. Undervisible-light photoredox conditions, selective cleavage of a C(&lt;em&gt;sp&lt;/em&gt;&lt;sup&gt;3&lt;/sup&gt;)–B bond in tetracoordinate boron speciesgenerates an alkyl radical that undergoes unprecedented long-distancemigration (1,4-, 1,5-, and the first 1,6-radical shift), with theincorporation of both radical and boron moiety into the products withcomplete atom economy─solving a long-standing problem in photoredoxdeboronations of alkyl tetracoordinate borons with boron species discardedas waste. Third, we explored the untapped potential of sequentialmultiple migrations on a single tetracoordinate boron atom. By judiciousselection of inducing reagents─identical or distinct electrophiles,bifunctional reagents, or transition-metal catalysts─two oreven three successive 1,2- and 1,3-migrations can be program","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 16","pages":"2745–2760"},"PeriodicalIF":18.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148675460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upgrading of Biomass-Derived Oxygen-Containing Chemicals for Nitrogen-Containing Chemicals: Moving from Nanoparticles to Single Metal Sites and Metal Oxides","authors":"Peng Zhou,&nbsp;Ziliang Yuan,&nbsp;Xixi Liu,&nbsp;Jie He,&nbsp;Zehui Zhang","doi":"10.1021/acs.accounts.6c00319","DOIUrl":"10.1021/acs.accounts.6c00319","url":null,"abstract":"&lt;p&gt;Highly valued N-containing compounds are importantand widely appliedin the agricultural, pharmaceutical, and material industries. Oxidativeor reductive coupling of oxygen-containing chemicals with ammoniaor amines is one of the most promising routes to access N-containingcompounds. Compared with carbonyl compounds (ketones and aldehydes),starting from alcohols for the synthesis of N-containing compoundsis much more challenging. The synthesis of N-containing compoundswith alcohols as the raw materials starts with the activation of alcoholsvia dehydrogenation or oxidation to produce aldehydes, which thencouple with nitrogen sources (e.g., amines, NH&lt;sub&gt;3&lt;/sub&gt;) to formimine intermediates. Imine intermediates can then be reduced to amines,oxidized to nitriles, or preserved. Integrating biomass alcohols,such as ethanol, into the N-containing compound supply chain can reducethe carbon footprint and enhance the economic competitiveness of biorefineries;however, activating the unreactive aliphatic α-C&lt;sub&gt;sp3&lt;/sub&gt;–H is challenging due to its high bond dissociation energy(94–96 kcal mol&lt;sup&gt;–1&lt;/sup&gt;). Another problem liesin the selective synthesis of chemicals bearing C═N bonds,including imines and &lt;em&gt;N&lt;/em&gt;-heterocycles. Therefore, activatingaliphatic biomass-derived alcohols for reductive or oxidative aminationto N-containing compounds, especially unsaturated ones, remains along-standing challenge.&lt;/p&gt;&lt;p&gt;To address this issue, we adopted anadsorption-oriented catalystdesign strategy. The electron-deficient active center is proposedto selectively adsorb and activate electron-rich nitro and hydroxylgroups while leaving the less polar C═N intermediate inert.This work pioneers a cost-effective pathway for upgrading biomassand synthesizing sustainable N-containing compounds.&lt;/p&gt;&lt;p&gt;In thisAccount, we summarize our recent efforts to design novelcatalysts for reductive or oxidative coupling of biomass-derived oxygen-containingchemicals and nitrogen sources, targeting N-containing compounds,especially imines and &lt;em&gt;N&lt;/em&gt;-heterocycles. We start bypresenting cases of positively charged single-atom catalysts for theconstruction of amines via base-free hydrogen transfer and extendtheir use to imine synthesis. Imines with lower polarity and moresteric hindrance at the C═N moiety desorb from single-atomsites readily, thereby retaining excellent selectivity. We furtherhighlight that reducible metal oxides are also active in reductivecoupling after oxygen vacancies are introduced, acting as positivelycharged active centers for adsorption. Structurally diverse iminesand &lt;em&gt;N&lt;/em&gt;-heterocycles can be obtained with satisfactoryyields. A nonreducible metal oxide also showed comparable activityif oxygen vacancies were introduced via size engineering. With theexcellent catalytic performance of single metal sites and defectivemetal oxides in the activation of alcohols, we also show that novelroutes for the oxidative coupling of alcohols were developed for thesynthesi","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 16","pages":"2662–2678"},"PeriodicalIF":18.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerated Chemistry in Microdroplets","authors":"R. Graham Cooks,&nbsp;Thalappil Pradeep","doi":"10.1021/acs.accounts.6c00099","DOIUrl":"10.1021/acs.accounts.6c00099","url":null,"abstract":"&lt;p&gt;We suggest that accelerated reactions in confinedvolumes, specificallyin microdroplets that contain water in contact with air, representa remarkable, indeed a revolutionary chemical phenomenon. This strongclaim is justified by the magnitude of the acceleration effect, byevidence for impact in key areas like reaction screening for drugdiscovery, by its alignment with sustainable chemistry and by therange of natural phenomena, including geological as well as atmosphericprocesses, where the effect operates. Accelerated processes in microdropletsenablethe rapid conversion of quartz microparticles into hydrophilic silicananoparticles, the late-stage functionalization of complex biomolecules,and the synthesis of heterocyclic compounds through rapid, environmentallybenign 'green' processes that contrast strongly with conventionalmetal-catalyzed routes.&lt;/p&gt;&lt;p&gt;The phenomenon is so unexpected, sounusual, that it has raisedskepticism ─ as indeed it should. Compelling evidence for itsoperation is found in automated high-throughput (HT) experiments inwhich thousands of reactions are carried out at rates of 1 reaction/secondand where accelerated processes occur in microdroplets generated fromreaction mixtures during their millisecond flight times to give productsthat are identified by online mass spectrometry (MS) or depositedon surfaces and then bioassayed. Additional evidence comes from earlystudies of organic ‘name’ reactions while parallel evidencefor just how remarkable this ‘water and air’ chemistryis comes from the transformations of N&lt;sub&gt;2&lt;/sub&gt;. This classicallyunreactive, diatomic molecule can be oxidized to NO&lt;sub&gt;2&lt;/sub&gt; orreduced to NH&lt;sub&gt;3&lt;/sub&gt; using nothing but the special interfacialproperties of wet microdroplets. The oxidation state of nitrogen rangesfrom +4 to −3 in these products, and intermediates with oxidationnumbers lying within this range are also observed. Just as remarkably,microparticles of minerals, suspended in microdroplets of water, arebroken down to generate nanoparticles simply by spraying the mixtureand collecting the spray. Evidence that Si–O bonds are cleavedby the superacidic character of the microdroplets stands in contrastwith the fact that nanomaterials can be built up by deposition ofsolvated ions ─ &lt;em&gt;both&lt;/em&gt; processes occurring insprayed microdroplets. Further evidence for the remarkable range ofchemistry that occurs under apparently mild conditions lies in thefact that amino acids can be &lt;em&gt;condensed&lt;/em&gt; to createpeptides in sprayed droplets, while other esters and PFAS ‘forever’chemicals can be rapidly &lt;em&gt;hydrolyzed&lt;/em&gt; in the same medium.&lt;/p&gt;&lt;p&gt;Microdroplet chemistry lies at the convergence of three chronologicallydistinct but methodologically intersecting domains: accelerated molecularreactions, interfacial inorganic chemistry, and materials evolutionunder nonequilibrium conditions. Each strand emerged independently,yet microdroplets provide a common physical platform in which theymerge through share","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 16","pages":"2603–2614"},"PeriodicalIF":18.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148595772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organocatalytic Enantioselective Electrophilic C–H Sulfenylation of Arenes","authors":"Yu-Xuan Huo,&nbsp;Zhi-Min Chen","doi":"10.1021/acs.accounts.6c00354","DOIUrl":"10.1021/acs.accounts.6c00354","url":null,"abstract":"&lt;p&gt;Electrophilic aromatic substitutionhas long served as a cornerstonefor C–H functionalization, yet its catalytic enantioselectivevariant, especially for sulfenylation, remains largely unexplored.The challenges are multifaceted: the stereogenic element often liesremote from the reaction site, multiple reactive sites compete, andthe mechanisms of asymmetric induction vary unpredictably with substratestructure. Overcoming these obstacles requires not only new catalystsbut also a deep understanding of the underlying stereochemical properties.In this Account, we summarize our systematic efforts to address theseobstacles through chiral Lewis base-catalyzed enantioselective electrophilicC–H sulfenylation of arenes, a metal-free approach that inherentlyavoids the catalyst poisoning issues common in transition-metal-mediatedC–S cross-couplings.&lt;/p&gt;&lt;p&gt;Starting from the atroposelectivesulfenylation of biaryl phenols,we discovered that a combined desymmetrization/kinetic resolutionsequence, enabled by chiral 1,1’-binaphthyl-2,2’-diol(BINOL)-derived selenide catalysts and an achiral sulfonic acid, deliversaxially chiral organosulfur products with high enantiocontrol. Thiswork established the feasibility of asymmetric aromatic sulfenylationand laid the groundwork for subsequent expansions. Mechanistic studies,including nuclear magnetic resonance (NMR) titrations, density functionaltheory (DFT) calculations, and noncovalent interaction (NCI) analysis,revealed that hydrogen-bond networks and π-π interactionsplay a crucial role in stabilizing the enantiodetermining transitionstates. The same catalytic logic was then extended to other substrateclasses, proving applicable to &lt;em&gt;N&lt;/em&gt;-aryl pyrroles andbiaryl anilines, with the latter proceeding via sole desymmetrization.For &lt;em&gt;N&lt;/em&gt;-aryl aminoquinones, the sulfide catalyst witha more rigid 1,1’-spirobiindane-7,7’-diol (SPINOL) backboneproved superior, affording chiral products with two contiguous C–Naxes. In addition to the synthesis of axially chiral organosulfurcompounds, we applied the same catalytic platform to construct planar-chiral,helically chiral, inherently chiral, and chiral silicon-stereogenicorganosulfur molecules. For planar-chiral cyclophanes, the mechanismswitches among dynamic kinetic resolution (DKR), kinetic resolution(KR), and desymmetrization depending on ring size. Helically chiralaza-[5]helicenes were obtained via DKR, and the sulfide products underwentcross-coupling without erosion of chirality. Inherently chiral calix[4]areneswere accessed through a rare example of chemoselective desymmetrizationwhere kinetic N-sulfenylation is reversible and gives way to thermodynamicallyfavored C-sulfenylation. Finally, chiral silicon-stereogenic cyclicdiarylsilanes were delivered through a tandem desymmetrization/kineticresolution sequence, further underscoring the generality of our approach.&lt;/p&gt;&lt;p&gt;Across all systems, noncovalent interactions such as C–H···π,π-π, and hydrogen bonding proved to be th","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 16","pages":"2709–2732"},"PeriodicalIF":18.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148650684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Affinity Peptide-Driven Precision Glycan Analysis: From Targeted Capture to Single-Molecule Profiling","authors":"Minmin Li,&nbsp;Guangyan Qing","doi":"10.1021/acs.accounts.6c00336","DOIUrl":"10.1021/acs.accounts.6c00336","url":null,"abstract":"<p>Glycansplay pivotal roles incell–cell communication, immunerecognition, signal transduction, and pathogen-host interactions.Their versatile functions stem from extraordinary structural diversity,defined by variations in composition, linkage, configuration, andbranching. Such structural complexity poses substantial challengesfor comprehensive glycan analysis. Complicating matters further, manyglycans exist only in trace amounts in biological systems, and theirnontemplate-driven biosynthesis precludes amplification. This dualconstraint further intensifies the analytical difficulties. Thus,the ability to isolate and structurally determine glycans with highefficiency has become paramount for advancing glycoscience.</p><p>Given the structural diversity of glycans, biological systems haveevolved a repertoire of glycan-binding proteins to decode these complexstructures. Lectins represent a prime example; renowned for theirspecific binding to glycans, they have been used to profile glycansin the form of affinity reagents. Inspired by lectins, we turned tothe rational design of glycan-affinity peptides (GAPs) that mimiclectin function. Over the past decade, our group has been dedicatedto the development of GAPs, driving their evolution from simple bindersto high-specificity, high-affinity recognition elements. These effortshave advanced GAPs from single amino acids and dipeptides to oligopeptides,accompanied by a remarkable affinity enhancement from millimolar tonanomolar levels. In parallel, the design paradigm has shifted fromempirical trial-and-error to directed evolution and now to preliminarycomputational design. As a result, these GAPs have evolved into versatileprecision recognition engines powering two complementary analyticalfrontiers: first, they underpin robust affinity materials for theprecision capture of glycosylated targets, including lipopolysaccharidesand circulating tumor cells; second, they enable high-resolution nanoporesensors capable of precision identification of specific glycans andglycosides. Overall, it is the evolution of GAPs into reliable recognitionplatforms that represents a significant advance in glycan analyticalcapability, moving from broad-spectrum enrichment toward targetedcapture, and from bulk measurements toward single-feature resolution.In this Account, we summarize our efforts in GAP design and applications,presenting a unified narrative of how we engineered these affinityengines to decipher the glycan code with high precision. We beginwith an overview of the fundamental principles, design strategies,and future trends underpinning GAP evolution. Following this, we detailour advances in GAP-driven precision glycan analyses. We believe thisAccount will drive the development of a new generation of GAPs andfacilitate their broader implementation across glycoscience.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 16","pages":"2679–2692"},"PeriodicalIF":18.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148675465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atomistic Simulations Decode the Mechanisms of DNA and RNA Processing Enzymes: Function through Motion","authors":"Marco De Vivo","doi":"10.1021/acs.accounts.6c00391","DOIUrl":"10.1021/acs.accounts.6c00391","url":null,"abstract":"&lt;p&gt;Enzymes and nucleic acid processingmachines are among the mostsophisticated molecules evolved by nature. These include several vitalenzymes such as polymerases, nucleases, topoisomerases, and RNA enzymes.These enzymes exhibit complex structures and multicomponent assembliesthat enable an exceptional efficiency and specificity in carryingout the fundamental chemical reactions required for life. Yet, thesestructures pose a challenge to our understanding of their catalyticprecision, as this requires atomistic insight into how they operateonDNA or RNA. Indeed, the static or quasi-static view from experimentsfails to fully explore the conformational space that these enzymestraverse during catalysis. Thus, advanced molecular simulation techniquesare increasingly integrated with experimental results to overcomesuch sampling limitations and to explore the configurational space,thereby defining the functional dynamics of structural motions andrearrangements that would otherwise remain unclear.&lt;/p&gt;&lt;p&gt;In thisAccount, I will examine how atomistic multiscale molecularsimulations and free energy calculations─recently coupled withAI-guided enhanced sampling methods─have contributed to clarifyingenzymatic mechanisms that could only be hypothesized by examiningstructures, as evidenced by increasingly complex structural biologyresults. This is a time when we can simulate ultralarge realisticmodel systems comprising proteins, nucleic acids, ions, and watermolecules, all of which are critical components for enzymatic function.Remarkably, such modeling and simulations can nowadays enable theprospective exploration of increasingly structurally complex systems.&lt;/p&gt;&lt;p&gt;In this scenario, there is today a relevant body of work that definesfunction through motion as a key element in these enzymes. My grouphas generated a broad collection of results on a range of nucleicacid processing enzymes, from polymerases to nucleases and RNA enzymes,which altogether highlight how &lt;em&gt;dynamics define function&lt;/em&gt;, with specific residues─often evolutionarily conserved andlocalized in the second coordination shell of the catalytic core─thatare strategically positioned to operate in a cooperative and highlycoordinated fashion for specific enzymatic actions on nucleic acids.These coordinated residue motions, near the reaction center, appeardistinct from large allosteric movements of distal domains. Instead,they resemble finely tuned, small-scale mechanisms that marry complexitywith the precise, clocklike efficiency evolution has built into thecatalytic core. How such elaborate enzymatic architectures &lt;em&gt;move-to-function&lt;/em&gt;, captured and demonstrated by the mostrecent computational work and structural data, will therefore be thecore topic discussed in this Account. While the concept of “&lt;em&gt;function through motion”&lt;/em&gt; can obviously be extendedto other catalytic systems, what is particularly remarkable aboutthese enzymes─even if not unique─is that their functionalcomplexity is handl","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 16","pages":"2733–2744"},"PeriodicalIF":18.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single Fluorogens and Orientation-Localization Microscopy for Quantifying Chemical and Biomolecular Dynamics at the Nanoscale","authors":"Yiyang Chen,&nbsp;Yuanxin Qiu,&nbsp;Matthew D. Lew","doi":"10.1021/acs.accounts.6c00353","DOIUrl":"10.1021/acs.accounts.6c00353","url":null,"abstract":"&lt;p&gt;Many chemical systems look uniformonly because ensemble measurementsaverage over their most interesting molecules. Electron-transfer ratesvary across electrode surfaces; lipid membranes contain nanodomainswith distinct packing and fluidity; peptide aggregates exhibit localpolymorphism; and biomolecular condensates contain transient networksof interactions that are blurred in ensemble images. A central challengein chemical imaging is not simply to see smaller structures, but tomeasure chemical variables such as polarity, redox potential, andmolecular confinement at the single-molecule level. In this Account,we describe how fluorogens, molecules whose brightness, blinking,spectral shifts, orientation, rotational mobility, and motion aredirectly shaped by their surroundings, can be integrated with single-moleculeorientation-localization microscopy (SMOLM) to produce multidimensionalimages of nanoscale chemistry.&lt;/p&gt;&lt;p&gt;The key idea is to treat a fluorophoreas a molecular sensor insteadof as a passive label. Its brightness and blinking can report localpolarity or redox state; its position identifies where the event occurs;its orientation and rotational freedom reveal local order and confinement;and its trajectory reports transport or local viscoelasticity. Byconstructing single-molecule (SM) polarization-sensitive microscopes,we measure molecular orientation and wobble alongside nanoscale positionand intensity. Thus, SMOLM provides the optical and computationalmachinery to extract multidimensional chemical observables from singlefluorogens.&lt;/p&gt;&lt;p&gt;We first highlight SM electrochemical imaging, inwhich redox-sensitivefluorophores report local midpoint potentials, revealing spatial variationsin electron-transfer behavior hidden by ensemble averaging and showinghow redox mediators can homogenize and shift fluorophore reduction.We then turn to lipid membranes, where solvatochromic lipophilic probessuch as Nile red and merocyanine 540 sense local packing, polarity,and fluidity. By measuring both rotational and translational dynamics,SMOLM shows that cholesterol-rich membrane regions can constrain molecularorientation while permitting heterogeneous, jump-like lateral motionand that cellular membrane curvature and composition generate spatiallyvarying orientational order.&lt;/p&gt;&lt;p&gt;In peptide and amyloid assemblies,transiently binding fluorogensconvert surface chemistry into nanoscale structural information. Nilered orientations report the alignment, disorder, and polymorphismof fibrillar architectures, distinguishing mature regions from newlydeposited or disordered branches and revealing helical bilayer-likeorganization that is inaccessible to position-only super-resolutionmicroscopy. Finally, we discuss biomolecular condensates, where environmentallysensitive fluorogens expose hidden nanoscale organization within dropletsthat often appear homogeneous by diffraction-limited imaging. SM trajectoriesidentify hydrophobic hubs, speed-resolved maps reveal confined","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 16","pages":"2693–2708"},"PeriodicalIF":18.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148675459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metal-Free Electrochemical Construction of Oxygen Heterocycles","authors":"Hugo Valdés,&nbsp;Belen Batanero","doi":"10.1021/acs.accounts.6c00306","DOIUrl":"10.1021/acs.accounts.6c00306","url":null,"abstract":"&lt;p&gt;Oxygen heterocycles are ubiquitous across chemistry─fromepoxides that underpin bulk materials and industrial manufacturingto five- and six-membered rings that populate natural products, fragrances,agrochemicals, dyes, and modern medicines. Yet, compared with N-heterocycles,O-heterocycles have historically received less systematic attentionin synthetic-method development. One reason is that oxygen’shigher electronegativity often renders these frameworks more reactiveand less straightforward to control under conventional conditions.Organic electrosynthesis provides a compelling platform to addressthis challenge: by using electrons as traceless redox reagents andcontrolling reactivity through potential or current, electrochemistryenables access to high-energy intermediates (radical-anions, radical-cations,“active halogen”, superoxide) under mild conditionsand often without stoichiometric oxidants or reductants. This Accountsummarizes electrosynthetic conceptions that repeatedly enable theconstruction─and, in several cases, editing─of oxygenheterocycles spanning three-, five-, and six-membered rings.&lt;/p&gt;&lt;p&gt;We first discuss three-membered oxiranes, emphasizing cathodicmanifolds that resemble Darzens-type closures initiated by C–Xbond reduction and electrogenerated bases (EGBs), as well as solvent-enabledradical pathways that become accessible only upon reaching the dianionstate of 1,2-dicarbonyls. These mechanistic thresholds are convenientlydiagnosed by cyclic voltammetry (CV), which serves throughout theAccount as a fingerprint for identifying when productive electron-transferpathways switch on. Complementary anodic epoxidations proceed viamediator-driven oxygen transfer, including iodide-derived “activeiodine”.&lt;/p&gt;&lt;p&gt;We then survey five-membered O-heterocycles(furans, dihydrofurans,butenolides, and mixed O,N/O,S rings), highlighting how cathodic andanodic routes deliver distinct synthetic leverage. Representativeadvances include anodic dimerizations to bioactive butenolides, dearomativespirocyclizations via chalcogen radicals, oxidative [3 + 2] annulationsto dihydrofurans, and mediator-enabled cyclizations (TEMPO, triarylamines,iodide) that convert simple feedstocks into densely functionalizedheterocycles with high selectivity.&lt;/p&gt;&lt;p&gt;Finally, we address six-memberedO-heterocycles-coumarins/δ-lactones,dioxane/dioxine frameworks, and O,N/O,S systems, where electrochemistryenables both ring construction and ring remodeling. Cathodic pathwaysinvolving electrogenerated superoxide can trigger Baeyer–Villiger/Dakin-typelactone formation and ring expansion to isocoumarins, while anodicoxidation in terpenoid settings can proceed through carbocationicpathways that induce rearrangement, ring contraction, or lactonization.Beyond ring construction, electrochemistry uniquely enables skeletalediting─most notably redox-triggered ring expansions to isocoumarinsand related lactones─by accessing rearrangement-prone radicalanions and cationic intermediates under mi","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 16","pages":"2647–2661"},"PeriodicalIF":18.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148595768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}