Accounts of Chemical Research最新文献

{"title":"Metal Element Multiple Bonding and Small Molecule Activation on Transition Metal Complexes Supported by Mono- and Dianionic Pentadentate Ligand Platforms","authors":"C. Christopher Almquist, Laurent Maron, Warren E. Piers","doi":"10.1021/acs.accounts.6c00563","DOIUrl":"10.1021/acs.accounts.6c00563","url":null,"abstract":"<p>Multidentate ligands have thepotential to provide stable platformsfor small molecule activation and transformation at metal centersby utilizing the chelate effect to discourage deactivation pathwaysinvolving ligand loss. Pentadentate ligands represent maximal chelationwhile still retaining one coordination site for binding and activatingsmall molecules. They also enable provision of a framework for stabilizinghighly reactive M═E (E = O, NR or CR<sub>2</sub>) or M≡E(E = O, N or CR) moieties that can couple or undergo atom transferreactions to external substrates. Here, a key feature of the pentadentatemotif is the prevention of facile loss of the ligand <em>trans</em> to the high trans effect ligands E.</p><p>The majority of pentadentateligands are based on oxidation resistant,neutral amine or pyridine type donors, rendering them L<sub>5</sub>-type ligands; the pentapyridyl (<strong>PY5</strong>) ligand familyintroduced by Stack and Feringa are archetypical examples. Necessarily,complexes of metal ions supported by these ligand types are positivelycharged and accessing higher oxidation states higher than M(II) orM(III) are challenging. For the past decade, our group has exploredmono- and dianionic analogues of this classic framework obtained byreplacing one or both 2,6-dipyridyl methyl arms in PY5 on the anchoringpyridyl donor with dipyrazolyl aryl borate units, converting themto monoanionic L<sub>4</sub>X (<strong>BPz</strong><sub><strong>2</strong></sub><strong>Py</strong><sub><strong>3</strong></sub>) or dianionic L<sub>3</sub>X<sub>2</sub> (<strong>B</strong><sub><strong>2</strong></sub><strong>Pz</strong><sub><strong>4</strong></sub><strong>Py</strong>) pentadentate platforms.</p><p>The incorporation of borates into the pentadentate framework hasimportant consequences that can be exploited for new chemistry. First,the metals that can be accommodated expand to include the early transitionmetals; L<sub>5</sub> type ligands are not effective for preparinggroups 3 and 4 metal complexes, so the anionic ligands are truly “pan-Periodic”.Second, complexes of these ligands with metals in higher oxidationstates are either neutral or monocationic, allowing highly reactiveM═E/M≡E species to retain solubility in nonpolar organicsolvents, facilitating detailed solution studies that map out speciationand enable mechanistic studies.</p><p>This Account will first elaborateand expand on the features andlimitations of pentadentate platforms in small molecule activationand reactive group stabilization. The advantages of incorporatingborate arms into the framework will then be illustrated through examplesfrom our extensive studies on the coordination chemistry of theseligands with elements from across the Periodic Table, focusing onthe first row transition metals. A rare example of a terminal scandiumimido and implication of a highly reactive iron(III) imidyl illustratethe ability of these ligands to generate six coordinate examples ofthese reactive functions.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 18","pages":"3006–3022"},"PeriodicalIF":18.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148858333","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":"Exploring the role of power during debriefing of interprofessional simulations.","authors":"Kathryn Robertson, Mindy Ju, Bridget C O'Brien, Sandrijn M van Schaik, Naike Bochatay","doi":"10.1080/13561820.2022.2029371","DOIUrl":"10.1080/13561820.2022.2029371","url":null,"abstract":"<p><p>Interprofessional simulation aims to improve teamwork and patient care by bringing participants from multiple professions together to practice simulated patient care scenarios. Yet, power dynamics may influence interprofessional learning during simulation, which typically occurs during the debriefing. This issue has received limited attention to date but may explain why communication breakdowns and conflicts among healthcare teams persist despite widespread adoption of interprofessional simulation. This study explores the role of power during interprofessional simulation debriefings. We collected data through observations of seven interprofessional simulation sessions and debriefings, four focus groups with simulation participants, and four interviews with simulation facilitators. We identified ways in which power dynamics influenced discussions during debriefing and sometimes limited participants' willingness to share feedback and speak up. We also found that issues related to power that arose during interprofessional simulations often went unacknowledged during the debriefing, leaving healthcare professionals unprepared to navigate power discrepancies with other members of healthcare teams in practice. Given that the goal of interprofessional simulation is to allow professionals to learn together about each other, explicitly addressing power in debriefing after interprofessional simulation may enhance learning.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"746-754"},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39881806","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":"Embracing or relinquishing sources of power in interprofessional communication: implications for patient-centered speaking up.","authors":"Susan E Farrell, Naike Bochatay, Sara Kim","doi":"10.1080/13561820.2021.1975665","DOIUrl":"10.1080/13561820.2021.1975665","url":null,"abstract":"<p><p>Health professionals working in an interprofessional work environment are entrusted to speak up on behalf of patients. However, that environment is comprised of dynamic intra- and interprofessional hierarchies, characterized by power differentials that affect speaking up behaviors. Drawing on the social bases of power and on power/interaction theory, we analyzed focus group and interview transcripts of 62 health professionals' accounts of speaking up. We focused on their primary sources of power, and described factors associated with health professionals' embracing power to speak up for patient safety, as well as those associated with relinquishing power and remaining silent. Nurses primarily employed direct patient information as a source of power to advocate for patients. Senior nurses and attending physicians exercised their legitimate power through titles or expertise, and when embracing that power, often influenced the healthcare team's speaking up behaviors and the team environment. Physician trainees perceived to have limited sources of power. Participants reported using hospital policies, relationships, and humor for engaging in speaking up behavior. Relinquishing power and remaining silent were associated with fear, anxiety, and lack of confidence. Given the complex, hierarchical environment in healthcare, leaders' inclusive behaviors for setting a culture for speaking up, including modeling speaking up, are critical.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"738-745"},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39866231","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":"Stimuli-Responsive Nanocoatings Enable Controlled Oral Delivery of Therapeutic Bacteria","authors":"Huan Chen,&nbsp;Xiao Kuang,&nbsp;Jinyao Liu","doi":"10.1021/acs.accounts.6c00272","DOIUrl":"10.1021/acs.accounts.6c00272","url":null,"abstract":"&lt;p&gt;Oral bacteriotherapy has givenrise to an unprecedented potentialin treating a variety of diseases, especially gastrointestinal tract-associatedimmune and metabolic disorders, through reversing microbial imbalance-inducedphysiological dysfunctions. However, living therapeutic bacteria areoften plagued by unsatisfactory treatment outcomes due to their impairedoral viability, unpredictable intestinal distribution, and undesiredin vivo colonization. Controlled delivery of therapeutic bacteriavia customized vehicles is able to overcome these difficulties byprotecting a bacteria from environmental insults, selectively releasingin the intestine, and/or increasing targeted accumulation at the lesionsite. Recently, remarkable efforts have been made on cell surfacemodification to improve the in vivo delivery of therapeutic bacteriabased on specific physiological environments and/or pathological features.Among these purposive modification strategies, the formation of astimuli-responsive nanocoating represents a versatile platform tointroduce bacteria with extra functions, such as enhanced resistance,site-specific exposure, and physiological signal-triggered in situactivation in the gastrointestinal tract, offering a promising approachfor precisely delivering therapeutic bacteria for advanced oral bacteriotherapy.&lt;/p&gt;&lt;p&gt;In this Account, we summarize the recent advances from our groupin manipulating bacterial behaviors through the construction of gastrointestinalstimuli-responsive nanocoatings, with the aim to enable controlledoral delivery of living therapeutic bacteria. First, we report theuse of available reactive moieties on the bacterial surface to formdiverse stimuli-responsive nanocoatings without affecting bacterialviability. By virtue of abundant intermolecular interactions, suchas electrostatic attraction, hydrophobic adsorption, π–πstacking, coordination bonding, or heterogeneous nucleation mineralization,nanocoatings consisting of functional small molecules, polymers, and/ornanoparticles can be formed on the bacterial surface. We describehow these nanocoatings can intelligently respond to specific gastrointestinalstimuli, thereby enabling the controlled oral delivery of modifiedbacteria. For instance, the introduction of a gastric acid-responsivenanocoating can neutralize acidic insult to enhance bacterial tolerance,ensuring the passage of intact bacteria through the stomach. Additionally,an enteric nanocoating can be triggered to dissolve in response topH fluctuation, consequently rendering a selective release of therapeuticbacteria in the intestine. Moreover, equipping bacteria with a pathologicalsignal-sensitive nanocoating enables the controllable exposure oftherapeutic bacteria at the lesion site, achieving targeted deliveryto the lesion site. Then, we show the advantages of stimuli-responsivenanocoating-enabled controlled oral delivery of therapeutic bacteriafor disease intervention. Specifically, we highlight the applicationsinvolving th","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 17","pages":"2761–2772"},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148692534","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":"Hierarchical Energy-Dissipating Networks: An Interaction-Level Design Principle for Tough, Stable, and Sustainable Elastomers and Ionogels","authors":"Nan Sun,&nbsp;Kaiqiang Zhang,&nbsp;Xu Wang","doi":"10.1021/acs.accounts.6c00425","DOIUrl":"10.1021/acs.accounts.6c00425","url":null,"abstract":"&lt;p&gt;Elastomeric materials are used where few otherpolymeric materialscan operate: in components that must deform repeatedly, recover rapidly,and continue to bear load under mechanical or environmental stress.Yet the molecular features that give elastomeric materials high performanceoften work against sustainability. The same interactions that makean elastomeric material reliable in service often make it difficultto heal or recycle. Weakening the network improves mobility but usuallyundermines the mechanical integrity that elastomeric materials areexpected to provide. Early studies on supramolecular elastomers demonstratedthat reversible hydrogen bonding, ionic association, metal–ligandcoordination, and other noncovalent motifs could impart thermoreversibility,self-healing capability, and stress relaxation behavior to materials.Covalent–supramolecular networks combine stable covalent backboneswith reversible physical associations, allowing mechanical integrityand local molecular mobility to be regulated at different structurallevels. Dynamic covalent networks, including vitrimers and other covalentadaptable networks, introduce exchangeable covalent bonds that enabletopology rearrangement, reshaping, repair, and reprocessing whilemaintaining network connectivity. The central design problem is thereforeto make network dynamics conditional: active enough to dissipate energyand enable reconstruction, but restrained enough to preserve integrityduring service. Our recent work addresses this question through hierarchicalenergy-dissipating networks (HEDNs). In HEDNs, supramolecular interactionsand covalent linkages are not simply combined; they are assigned differentmechanical roles and activated at different stages of deformationor processing. Under deformation, weaker interactions dissociate firstto dissipate energy, while stronger interactions and covalent frameworkspreserve network integrity. During healing, reprocessing, or upcycling,reversible interactions provide the mobility and adaptability neededfor network reconstruction and component integration. Thus, hierarchicalenergy dissipation serves not only as a toughening mechanism, butalso as a molecular strategy for coordinating mechanical robustness,structural stability, and sustainable reuse.&lt;/p&gt;&lt;p&gt;This Account highlightsthree roles of this strategy in our studiesof supramolecular elastomers and ionogels. In thermoplastic elastomers,staged supramolecular dissociation allows stress to be dissipatedwithout destroying the load-bearing framework, leading to exceptionalstrength and toughness. In chemically cross-linked elastomers, covalentframeworks and reversible motifs divide the roles of stability andreconfiguration, enabling thermoset-like robustness together withthermal healing and reprocessing. In postservice materials, preinstalledinteraction sites further allow discarded elastomers or ionogels toaccommodate ionic liquids, carbon nanotubes, and other functionalcomponents, turning recycling into f","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 17","pages":"2816–2827"},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148717957","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":"Synthetic Framework Evolution: A Scaffold-Centric Perspective on Iterative Chemical Space Expansion","authors":"Kalliopi Mazaraki,&nbsp;George Karageorgis,&nbsp;Alexandros L. Zografos","doi":"10.1021/acs.accounts.6c00382","DOIUrl":"10.1021/acs.accounts.6c00382","url":null,"abstract":"&lt;p&gt;The efficient exploration of natural product-likechemical spaceremains a central challenge in synthetic chemistry and chemical biology.Despite major advances, many synthetic strategies remain organizedaround individual targets or predefined compound collections, whichcan limit the continuity and cumulative expansion of chemical spaceexploration across successive synthetic campaigns. Developing approachesthat enable sustained, scalable, and unbiased expansion of biologicallyrelevant molecular diversity is therefore a key objective for modernsynthesis.&lt;/p&gt;&lt;p&gt;Here, we formalize Synthetic Framework Evolution(SFE) as a scaffold-centricconceptual framework that organizes synthetic planning in terms ofpersistence, connectivity, and growth. Building upon emerging conceptsin bioinspired chemical divergence and scaffold evolution, SFE directsretrosynthetic analysis toward the identification of information-richintermediates that function as reusable nodes within an evolving syntheticnetwork. Rather than converging on isolated end points, synthesisis organized around persistent scaffolds that enable iterative divergenceand cumulative expansion of interconnected molecular architectures.&lt;/p&gt;&lt;p&gt;We demonstrate the implementation of SFE in sesquiterpenoid synthesis,a natural product family whose biosynthetic diversity provides anideal platform for framework-based design. Central to this approachis the hierarchical organization of conformationally flexible, low-oxidation-statescaffolds that encode latent reactivity and stereochemical information.These intermediates enable access to multiple carbocyclic frameworksthrough controlled rearrangements, cyclizations, and functional groupinterconversions, allowing structurally distinct natural product familiesto emerge from unified and continuously expandable synthetic pathways.&lt;/p&gt;&lt;p&gt;Beyond scaffold-level divergence, SFE incorporates oxidative transformationsas a second, amplifying dimension of chemical space generation. Inthis context, oxidation is not treated as a terminal functionalizationstep, but as a generative process that unlocks new topologies throughrearrangements, cascade reactions, and bond reorganization, closelyreflecting biosynthetic oxidative phases. In this sense, SFE placesoxidative diversification alongside scaffold rearrangement as a complementaryand generative driver of chemical space expansion. The integrationof these two layers, scaffold persistence and oxidative amplification,enables the efficient construction of structurally complex and denselyconnected regions of chemical space from a limited set of intermediates.&lt;/p&gt;&lt;p&gt;Cheminformatic analysis reveals that SFE-derived compounds occupybroad and biologically relevant regions of chemical space, exhibitinghigh natural product-likeness, shape diversity, and molecular complexityrelative to their size. In contrast to established paradigms suchas BIOS, DOS, and CtD, which often focus on the generation of discretecollections or predefined diversificat","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 17","pages":"2785–2799"},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148564789","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":"Continuous-Flow Electrosynthesis beyond Scaleup","authors":"Tian-Sheng Chen,&nbsp;Hao Long,&nbsp;Hai-Chao Xu","doi":"10.1021/acs.accounts.6c00485","DOIUrl":"10.1021/acs.accounts.6c00485","url":null,"abstract":"<p>Organic electrosynthesis hasemerged as a powerfulplatform forsustainable molecular synthesis, while continuous-flow electrochemistryis often viewed primarily as a technology for process intensificationand scaleup. In our studies, however, we have found that the significanceof continuous-flow electrochemistry extends far beyond improved productivity.The unique reaction environments created by single-pass flow electrolysis─includingshort residence times, spatially evolving electrochemical conditions,efficient mass transfer, and distinctive electrode interfacial microenvironments─canfundamentally alter reaction outcomes and facilitate transformationsthat are difficult to achieve in conventional batch reactors.</p><p>In this Account, we summarize our efforts in developing continuous-flowelectrosynthesis as a synthetic platform for challenging oxidativemolecular transformations. We first show how single-pass flow electrolysissuppresses undesired secondary electrode reactions, enabling selectiveoxidative cyclizations, C–H oxygenation, and C–H aminationreactions. We then discuss how continuous-flow electrolysis expandsthe accessible reactivity space of electro-oxidation by promotingproductive utilization of highly reactive intermediates, exemplifiedby sulfur-centered radical chemistry and phosphorus radical cationchemistry. Particular emphasis is placed on electrochemical microenvironmentengineering, where local ion distributions and acid–base propertieswithin the electric double layer can be exploited to control reactivity.We further demonstrate how these concepts culminate in electro-oxidativeasymmetric catalysis, where continuous-flow electrolysis providesan expanded operational window for simultaneously optimizing electrochemicaland stereochemical parameters.</p><p>Finally, we describe the translationof these transformations fromlaboratory-scale reactions to continuous production through reactornumber-up and process integration. We anticipate that the next phaseof development in flow electrosynthesis will be driven as much byadvances in reactor engineering as by advances in synthetic methodology,ultimately enabling increasingly sophisticated continuous and electrifiedmanufacturing platforms.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 17","pages":"2828–2842"},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148822360","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":"Detectability of feeding arteries using automated feeding artery detection software based on computed tomography arteriography in transarterial embolisation.","authors":"Takatoshi Kubo, Yasuaki Arai, Miyuki Sone, Takatsugu Magara, Shunsuke Sugawara, Masahiko Kusumoto, Osamu Abe","doi":"10.11622/smedj.2022060","DOIUrl":"10.11622/smedj.2022060","url":null,"abstract":"","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"571-574"},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44404419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative Flow Electrochemistry: A Platform for Generating Reactive Intermediates and Reaction Control","authors":"Sagar Arepally,&nbsp;Tribani Boruah,&nbsp;Rebecca L. Melen,&nbsp;Thomas Wirth","doi":"10.1021/acs.accounts.6c00413","DOIUrl":"10.1021/acs.accounts.6c00413","url":null,"abstract":"<p>Oxidative electrochemistry providesdirect access to highly reactiveintermediates under mild and sustainable conditions, yet controllingreactivity remains a central challenge in synthesis. In batch electrochemicalsystems, short-lived radicals, electrophilic oxidants, and cationicintermediates often undergo overoxidation, decomposition, or competingside reactions because of inefficient mass transfer and poor thermalcontrol. Continuous-flow electrochemistry addresses many of theselimitations by enabling rapid intermediate generation, efficient masstransport, precise residence-time control, and intensified reactionenvironments. In this Account, we describe how oxidative flow electrochemistrycan serve as a platform for controlling reactive intermediates throughselective generation and interception under continuous-flow conditions.Emphasis is placed on oxygen-centered radicals and reactive oxygenspecies, selenium electrophiles and radicals, electrophilic halogenand hypervalent iodine intermediates, heteroatom-centered oxidativecoupling processes, and stereoselective electrochemical transformationsthrough memory of chirality. Across these studies, a common principleemerges in which reaction selectivity is governed not only by thenature of the intermediate itself, but also by how fast and preciselyit is generated, transported, and trapped within the flow reactor.Mechanistic investigations, automation strategies, online analysis,and scalable electrochemical platforms further demonstrate how flowelectrochemistry enables a transition from empirical oxidative synthesistoward controllable and predictable reactive intermediate chemistry.Collectively, these studies establish oxidative flow electrochemistryas a versatile platform for reaction control and highlight its futurepotential in sustainable synthesis, asymmetric electrosynthesis, andautomated reaction development.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 17","pages":"2800–2815"},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805848","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":"SARS-CoV-2 Papain-Like Protease: Drug Design, Assay Development, and Drug Resistance","authors":"Jun Wang,&nbsp;Kan Li,&nbsp;Bin Tan","doi":"10.1021/acs.accounts.6c00361","DOIUrl":"10.1021/acs.accounts.6c00361","url":null,"abstract":"&lt;p&gt;SARS-CoV-2 papain-like protease(PL&lt;sup&gt;pro&lt;/sup&gt;) is a compellingbut historically underdeveloped antiviral target. Unlike the viralmain protease (M&lt;sup&gt;pro&lt;/sup&gt;), which rapidly became the focus ofintensive drug-discovery efforts and yielded clinical candidates andapproved drugs, PL&lt;sup&gt;pro&lt;/sup&gt; posed a more challenging medicinalchemistry problem: a shallow, flexible substrate-recognition surfaceand a mobile BL2 loop. Nevertheless, PL&lt;sup&gt;pro&lt;/sup&gt; is a high-profiledrug target because it is vital for viral replication by processingviral polyproteins and suppresses host innate immunity through deubiquitinatingand deISGylating activities. These dual functions make PL&lt;sup&gt;pro&lt;/sup&gt; more than a viral protease; it is a multifunctional immune-evasionenzyme whose inhibition could both block virus replication and restoreantiviral host responses.&lt;/p&gt;&lt;p&gt;This Account summarizes our group’seffort to convert PL&lt;sup&gt;pro&lt;/sup&gt; from a challenging target intoa tractable antiviral drug-discoveryplatform. We began by developing and applying orthogonal assays toidentify specific PL&lt;sup&gt;pro&lt;/sup&gt; inhibitors and triage false positives.High-throughput screening and drug-repurposing campaigns yielded earlyhits, including &lt;strong&gt;Jun9722&lt;/strong&gt;, &lt;strong&gt;Jun9754&lt;/strong&gt;, and tropifexor,but also revealed that biochemical inhibition alone was insufficientto predict cellular antiviral activity. This motivated us to developa FlipGFP cell-based reporter assay as a BSL-2-compatible bridge betweenenzymology and live-virus studies. In addition, we later developeda fluorescence polarization assay using a fluorescein-labeled PL&lt;sup&gt;pro&lt;/sup&gt; ligand to enable direct, high-throughput quantificationof inhibitor binding. Together with FRET enzymatic assays, thermalshift experiments, cellular FlipGFP assays, and antiviral assays,these tools established a rigorous validation framework for PL&lt;sup&gt;pro&lt;/sup&gt; medicinal chemistry.&lt;/p&gt;&lt;p&gt;With this platform in place,we pursued structure-based PL&lt;sup&gt;pro&lt;/sup&gt; inhibitor design. Earlycocrystal structures showed thatpotent noncovalent inhibitors engage the BL2 groove and stabilizeinhibitor-bound PL&lt;sup&gt;pro&lt;/sup&gt; conformations. A major conceptualadvance came from structural analysis of the &lt;strong&gt;Jun11313&lt;/strong&gt;-bound PL&lt;sup&gt;pro&lt;/sup&gt; complex, which revealed that an inhibitorsubstituent occupied a hydrophobic surface pocket corresponding tothe Val70 position of ubiquitin. We designated this newly recognizedregion the Val70&lt;sup&gt;Ub&lt;/sup&gt; pocket. Exploiting this pocket transformedPL&lt;sup&gt;pro&lt;/sup&gt; inhibitor design by expanding ligand engagement beyondthe canonical BL2 groove and enabling substantial gains in enzymaticinhibition and antiviral activity.&lt;/p&gt;&lt;p&gt;This design principle ledto orally active noncovalent inhibitors,including &lt;strong&gt;Jun12682&lt;/strong&gt; and the quinoline lead &lt;strong&gt;Jun13296&lt;/strong&gt;, both of which showed potent enzymatic inhibition, cellular antiviralactivity, favorable mouse pharmacokinetics, and protection in SARS-CoV-","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 17","pages":"2773–2784"},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805846","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}