Accounts of Chemical Research最新文献

{"title":"Revealing Mechanisms in the Early Stages of Virus Infection by Single-Virus Tracking.","authors":"Lei Du,Li-Juan Zhang,Dai-Wen Pang","doi":"10.1021/acs.accounts.5c00491","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00491","url":null,"abstract":"ConspectusUnraveling the mechanisms of viral infection is crucial for controlling viral transmission and treating viral diseases. Viral infection exhibits highly complex and dynamic processes, involving diverse infection routes, multistep infection procedures, intricate interactions with host cellular components, and even spatiotemporal changes in the hierarchical structure of viral particles. Many critical biological events, such as viral entry, trafficking, and replication, can occur within seconds to minutes. Conventional virology techniques predominantly provide static, averaged information, often failing to accurately capture the dynamic features of viral infection.The advent of dynamic imaging technologies has ushered in a new era for virology research. Among these, single-virus tracking (SVT) represents a revolutionary breakthrough, enabling real-time visualization of individual fluorescently labeled virions using fluorescence microscopy. By reconstructing and statistically analyzing biomolecular trajectories with high spatiotemporal resolution, this approach yields quantitative insights into their dynamic behavior. In contrast to conventional virological methods, SVT offers three key advantages: (1) precise localization of individual viral trajectories during infection, (2) dynamic monitoring of virus-host interactions, and (3) focusing on specific steps in the viral infection. This cutting-edge technique has already demonstrated remarkable success in elucidating the mechanisms of viral infection, providing an unprecedented perspective for understanding viral infection processes.In this Account, we focus on the key problems addressed by dynamic imaging technology, particularly its applications in virology, and discuss how it enables critical discoveries and the key mechanisms of viral infection revealed using this technology. Specifically, we provide an in-depth analysis of three pivotal biological processes during viral infection: (1) the molecular mechanisms of viral entry into host cells, (2) intracellular transport of viral particles, and (3) the dynamic processes of membrane fusion and genome release. Building upon previous research, we present, for the first time, a systematic and comprehensive dynamic landscape of the early stages of viral infection, as revealed by SVT. Through representative case studies, we highlight the remarkable analytical power and broad applicability of dynamic imaging techniques in deciphering molecular mechanisms of biological processes. Finally, we discuss future challenges and directions in this field, highlighting the critical role of interdisciplinary approaches. We envision that enhanced collaboration across physics, chemistry, and life sciences will accelerate SVT's innovative applications in biomedical research and inspire novel strategies for uncovering unexplored mechanisms.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"29 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209313","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":"Precision Phototherapy Enabled by Decoding Complex Microenvironments.","authors":"Qihang Ding,Manlin Qi,Wen Li,Meiqi Li,Jiling Xu,Yujin Kim,Goeun Kim,Biao Dong,Lin Wang,Jong Seung Kim","doi":"10.1021/acs.accounts.5c00488","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00488","url":null,"abstract":"ConspectusThe complex and dynamic microenvironments of pathological sites, including infections, tumors, and neurological disorders, impose formidable challenges on conventional therapies due to features such as iron dysregulation, localized acidity, biofilm barriers, and thermal adaptation. Harnessing these microenvironmental cues to design light-activated, microenvironment-responsive therapeutic platforms offers a promising strategy for precise, spatiotemporally controlled treatments.Nutritional immunity restricts iron availability to suppress pathogen proliferation, while bacteria deploy specialized siderophore-mediated uptake systems to circumvent this restriction. By exploiting this vulnerability, \"Trojan horse\" nanoplatforms such as a multifunctional nanocomposite (Ga-CT@P) can hijack bacterial iron uptake pathways, induce iron starvation, and exert potent antimicrobial effects. DFT calculations revealed that Ga3+ exhibits stronger, more uniform binding to enterobactin than Fe3+, leading to stable, redox-inert complexes that mislead bacterial transport systems.Beyond metal ion interference, acid-responsive photodynamic therapy (PDT) offers spatiotemporally precise activation at infectious sites while minimizing off-target toxicity. Our development of DHTPA, a pH-responsive AIE photosensitizer, enables robust reactive oxygen species (ROS) generation exclusively under mildly acidic conditions, enhancing bactericidal efficacy. This platform demonstrated strong antibacterial effects against drug-resistant pathogens and effectively promoted wound healing in vivo, showcasing the potential of lesion-specific \"on-demand\" PDT.To address biofilm barriers, OMV-camouflaged nanodisguisers synergistically integrate photothermal heating, ion interference, and ROS generation to dismantle biofilms while inducing metabolic collapse in pathogens. Simultaneously, OMV-coated nanodisguisers exploit bacterial adhesion pathways for targeted delivery, enabling photonic disruption of pathogen metabolism.In thermosensitive microenvironments, where heat-shock-protein-mediated thermal tolerance limits photothermal therapy (PTT), we developed dual-laser PTT strategies using NIR-II AIEgens (PM331@F127) to achieve precise, stepwise thermal regulation. This strategy rapidly suppresses heat tolerance mechanisms at higher temperatures and maintains moderate thermal ablation, maximizing efficacy while reducing collateral damage.In high-barrier systems such as the central nervous system (CNS), crossing the blood-brain barrier (BBB) is essential for effective phototherapy. We designed DK@RA-PEG, an NIR-II photosensitizer platform functionalized with RVG peptides and nucleic acid aptamers, to enable BBB penetration, virus-specific targeting, and ROS-mediated viral eradication under NIR light. This approach demonstrated effective treatment of rabies virus infection in vivo while maintaining neurocompatibility.Collectively, these advances establish a versatile framework for microe","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"157 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203883","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":"Molecular Insights into Bismuth's New Applications against Antimicrobial Resistance and Coronaviruses.","authors":"Hongyan Li, Xueying Wei, Hongzhe Sun","doi":"10.1021/acs.accounts.5c00471","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00471","url":null,"abstract":"<p><p>ConspectusBismuth, a heavy metal distinguished by its low toxicity, compared to lead or mercury, has long been associated with medicine for the treatment of various conditions, notably as a key component in triple and quadruple therapies for eradicating <i>Helicobacter pylori</i>, including antibiotic-resistant strains. Compounds such as bismuth subsalicylate (BSS) and colloidal bismuth subcitrate (CBS) enhance the efficacy of antibiotics, e.g., metronidazole and tetracycline. Over the past two decades, the knowledge on the molecular mechanism of action of bismuth drugs has been significantly advanced, in particular with the aid of the metallomics/metalloproteomics, facilitating the discovery of novel therapeutic applications beyond <i>H. pylori</i> eradication.This Account describes how the molecular mechanism of action of bismuth drugs was unveiled at a system level by multiple-metalloproteomics approaches, which enable the comprehensive identification of bismuth-binding proteins with diverse affinities in bacteria. By integration with other techniques such as proteomics, bioinformatics and molecular biology, the sustained efficacy of bismuth drugs was attributable to their capacities to disrupt multiple biological pathways through binding and functional perturbation of key enzymes, in particular, those enzymes bearing C<i>X</i><sub><i>n</i></sub>C (<i>n</i> = 2, 7), C<i>X</i><sub><i>n</i></sub>H (<i>n</i> = 5, 6) and H<i>X</i><sub><i>n</i></sub>H (<i>n</i> = 0-2, 8) motifs, in consistence with the thiophilic nature and high acidic property of bismuth.The generated knowledge on the mode of action of bismuth drugs lays a solid foundation for further exploration of their novel therapeutic applications. Our extensive studies have revealed that bismuth drugs and compounds hold great potential as versatile agents in combating antimicrobial resistance (AMR) crisis through co-therapies with clinically used antibiotics. This includes bismuth drugs as broad-spectrum inhibitors of metallo-β-lactamases (MBLs), enzymes responsible for resistance to β-lactam antibiotics, to fight against MBLs-positive bacterial infection together with β-lactams; bismuth drugs serve as adjuvants of Cefiderocol (Fetroja), the only clinically approved sideromycin, against infections caused by multidrug-resistant <i>Pseudomonas aeruginosa</i> and <i>Burkholderia cepacia</i>; bismuth drugs (and relevant compounds) in combination with clinically used antibiotics could combat <i>Pseudomonas aeruginosa</i> infections by disrupting iron homeostasis and functionally impairing Fe-S cluster-containing enzymes in multidrug-resistant <i>Pseudomonas aeruginosa;</i> newly developed bismuth compounds serve as novel metalloantibiotics to combat AMR. Moreover, the ability of bismuth to disrupt key zinc finger proteins for the transcription and replication in coronavirus rendered its new potential in treating coronavirus infections, particularly SARS-CoV-1 and SARS-CoV-2. Combining clini","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":17.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204980","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":"Mental Healthcare Providers Understanding and Experiences of Palliative Care: A Qualitative Analysis.","authors":"Tanya Park, Lydia Mutoni, Ramya Sridhar, Kathy Hegadoren, Bernadette Workun","doi":"10.1177/08258597221134865","DOIUrl":"10.1177/08258597221134865","url":null,"abstract":"<p><p><b>Objective:</b> To understand the experiences and perceptions of mental health providers about palliative care. <b>Background:</b> Little attention is paid to the experience of people with chronic persistent mental illness (CPMI) and life-threatening diseases and how their dying experience might differ from those without a CPMI. <b>Methods:</b> Interpretive description informed the project. Sixteen mental health care providers were interviewed using a semi-structured interview template. The interviews were recorded, transcribed, and analyzed using a reflexive, inductive-deductive thematic approach, guided by Braun & Clarke's framework for thematic analysis. <b>Results:</b> Four themes were identified from the data: intersectionality, limited collaboration, misconceptions about palliative care, and relationships. Mental health providers identified gaps in their knowledge of palliative care practices along with their knowledge of death and dying.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"322-328"},"PeriodicalIF":17.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12318162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40562849","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":"L-RNA Aptamer-Based Tools for G-Quadruplex Structure: Identification, Characterization, and Application.","authors":"Danyang Ji,Kun Zhang,Maryana Yarshova,Chun Kit Kwok","doi":"10.1021/acs.accounts.5c00468","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00468","url":null,"abstract":"ConspectusAptamers are single-stranded DNA or RNA oligonucleotides that bind specifically and strongly to their target molecules. However, the inherent instability of natural DNA and RNA aptamers in biological environments limits their applications. To overcome this limitation, we focused on the development and application of L-RNA aptamers composed of unnatural L-RNA nucleotides. The mirror stereochemistry of L-RNA confers enhanced stability against nuclease degradation, making it an ideal candidate for molecular targeting and biological applications. In addition, L-RNA's inability to hybridize with D-DNA/RNA through Watson-Crick base pairing enables the selection of aptamers based on structure recognition. Our group focuses on targeting functional G-quadruplex (G4) structures that play critical roles in various cellular processes, including DNA replication, transcription, and translation, and are implicated in diseases such as cancers, neurological disorders, and viral pathogenesis.This Account highlights our group's recent efforts in developing novel and robust L-RNA aptamer selection platforms and tools for targeting functionally important G4 structures in different biological systems. Pioneering the L-RNA aptamer selection method for G4 structures, we have further established additional selection platforms enhancing SELEX (Systematic Evolution of Ligands by EXponential enrichment) efficiency, as well as binding affinity and specificity for G4 targets. Following lead aptamer identification and characterization using various biophysical and biochemical tools, our group has explored a number of innovative post-SELEX modification strategies to further improve the L-RNA aptamer's functionality. Such include the development of circular L-RNA aptamers, L-RNA aptamer-antisense oligo (ASO) conjugates, L-RNA aptamer-fluorogenic RNA aptamer conjugates, and L-RNA aptamer-peptide conjugates for various in vitro, in-cell, and in vivo applications. From our studies, we have reported that these L-RNA aptamers can effectively regulate G4-mediated cellular processes by inhibiting G4-protein interactions and/or modulating transcription and translation and ultimately influencing gene expression and beyond.Together, these works have advanced the accessibility, efficiency, and robustness of L-RNA aptamer technology, offering significant potential for the diagnosis and therapeutics of various diseases, particularly those related to G4 dysregulation. Our ongoing research seeks to further refine L-RNA aptamer selection, structure characterization, post-SELEX modification strategies, and their applications in biological and therapeutic contexts.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"69 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194502","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":"Advancing Genetically Encoded Lysine (GEK) Chemistry: From Precision Modulation to Therapeutic Innovation","authors":"Guoqing Jin, Yifan Shi, Shivangi Sharma, Wenshe Ray Liu","doi":"10.1021/acs.accounts.5c00401","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00401","url":null,"abstract":"Genetically encoded lysine (GEK) chemistry has transformed protein engineering by enabling precise and site-specific modifications, which expand lysine’s functional landscape beyond its native post-translational modifications (PTMs). Our work has systematically advanced GEK chemistry by developing engineered pyrrolysyl-tRNA synthetase (PylRS) variants that efficiently incorporate diverse lysine (Lys) derivatives with tailored chemical reactivity. By integrating bioorthogonal handles, acyl and electrophilic warheads, photo-cross-linking groups, and PTM mimics, we have established a set of powerful toolkits for protein labeling, functional studies, and Lys-directed drug design. These advances provide precise control over protein structure and function, facilitating the study of epigenetic modifications, enzyme–substrate interactions, and Lys-guided inhibitor development. As GEK chemistry continues to evolve, its integration with structural/synthetic biology and therapeutic innovation will further expand its impact, unlocking new frontiers in chemical biology and precision therapeutics.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"155 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153927","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":"High-Pressure Synthesis of Pnictogen Nitrides","authors":"Matteo Ceppatelli, Manuel Serrano-Ruiz, Marta Morana, Kamil Dziubek, Demetrio Scelta, Roberto Bini, Maurizio Peruzzini","doi":"10.1021/acs.accounts.5c00309","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00309","url":null,"abstract":"Nitrides represent a class of chemical compounds of high scientific and technological relevance. Nevertheless, due to the challenging synthetic conditions, essentially related to the stability of the N₂ molecule, nitrides have remained largely unexplored compared with the corresponding oxides.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"1 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154086","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":"Oriented Electric Fields─Universal Catalysts.","authors":"Sason Shaik, David Danovich, Surajit Kalita, Kshatresh D Dubey","doi":"10.1021/acs.accounts.5c00508","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00508","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusThis Account outlines principles of electric-field-mediated chemistry, whereby oriented-external electric fields (OEEFs) function as universal \"reagents\" that control reactivity/selectivity and structures of molecules/clusters. The TOC graphics illustrate the rate-enhancing OEEFs for two different reactions. For the Diels-Alder reaction, we also mark the corresponding reaction-axis (&lt;b&gt;RA&lt;/b&gt;). The &lt;b&gt;RA&lt;/b&gt; arrow specifies the &lt;b&gt;directional-flow, of the electron density and bond-coupling&lt;/b&gt;, from reactants to products (&lt;b&gt;RC&lt;/b&gt;→&lt;b&gt;PC&lt;/b&gt;). Determining the &lt;b&gt;RA&lt;/b&gt; direction, for a given process, involves curly arrow-pushing in the charge-transfer direction. By convention, the arrowhead of the &lt;b&gt;RA signifies the direction of the negative charge flow&lt;/b&gt; (Scheme 2). The arrowhead of the &lt;i&gt;&lt;b&gt;F&lt;/b&gt;&lt;/i&gt;&lt;sub&gt;&lt;b&gt;Z&lt;/b&gt;&lt;/sub&gt; (OEEF) vector is marked as positive, hence corroborating the direction of negative charge flow, which will be induced by &lt;i&gt;&lt;b&gt;F&lt;/b&gt;&lt;/i&gt;&lt;sub&gt;&lt;b&gt;Z&lt;/b&gt;&lt;/sub&gt;.Thus, as the Account demonstrates, &lt;i&gt;the impact of OEEFs on reactions and structural transformations is unique&lt;/i&gt;. &lt;b&gt;Energy-barriers-lowering generally occurs along a single direction in space&lt;/b&gt;, specified by the &lt;b&gt;RA&lt;/b&gt;. Furthermore, &lt;b&gt;the OEEF also catalyzes reactions in the presence of solvents&lt;/b&gt;! For example, the computed OEEF lowers the barrier of the Menshutkin reaction (pyridine/CH&lt;sub&gt;3&lt;/sub&gt;-I) by 10.6-12.6 kcal/mol in the three polar solvents. Thus, &lt;b&gt;solvent screening of the OEEF is imperfect&lt;/b&gt; &lt;i&gt;(see F&lt;/i&gt;&lt;sub&gt;&lt;i&gt;solvent-induced&lt;/i&gt;&lt;/sub&gt; &lt;i&gt;in the conspectus art)&lt;/i&gt;, and hence, chemical reactions are not limited to gas- or solid-phases. As the main text elaborates, &lt;b&gt;this imperfect screening-effect in solution is fundamental&lt;/b&gt;, and applicable to reactions and to OEEF-induced structural changes. &lt;b&gt;As such, the OEEF is a universal enhancer of chemical change&lt;/b&gt;.The Account starts with conceptual principles for understanding and predicting the theoretically computed and/or experimentally observed OEEF effects on chemical reactions as well as structural transformations. These principles highlight the role of OEEFs as &lt;b&gt;tweezers&lt;/b&gt; &lt;i&gt;&lt;b&gt;that orient molecular species&lt;/b&gt;&lt;/i&gt; &lt;b&gt;along the respective RAs&lt;/b&gt;, and accelerate their transformation to products.Subsequently, the paper describes experimental support of the theoretical results and guidelines. &lt;b&gt;Some of the applications also use continuous-flow setups, which&lt;/b&gt; &lt;i&gt;&lt;b&gt;will eventually scale-up product yields to Molar concentrations&lt;/b&gt;&lt;/i&gt;, and render &lt;i&gt;OEEFs as practical tools in chemistry&lt;/i&gt;. Evidence is presented for the potential existence of &lt;b&gt;OEEF/thermal dichotomy&lt;/b&gt;, wherein &lt;b&gt;the OEEF-induced products differ from those which are produced corresponding thermal-only reactions&lt;/b&gt; (see later work by Matile et al.).The paper addresses also an important structural process; on the type of EEF (oscillating vs static), which carries out most effectively the decompo","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":""},"PeriodicalIF":17.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147038","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":"Advances in Proximity-Assisted Bioconjugation","authors":"Mary Canzano, Gonçalo J. L. Bernardes","doi":"10.1021/acs.accounts.5c00368","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00368","url":null,"abstract":"Proximity-induced chemistry (PIC) refers to the transient reactivity between two or more molecules upon physical closeness which are otherwise unreactive. Harnessed by nature to control fundamental biological processes such as transcription and signal transduction, PIC increases the probability of correctly oriented, effective collisions, facilitating fundamental cellular processes. Within the field of chemical biology, PIC has been employed for several clinically relevant purposes, including the degradation of aberrant biomolecules and construction of protein therapeutics. This Account focuses on the application of PIC strategies for the development of site-specific bioconjugation techniques, termed proximity-assisted bioconjugation (PAB). Site-specific bioconjugation refers to the precise modification of biomolecules to generate homogeneous products. Such techniques are vital for the development of protein therapeutics including antibody–drug conjugates (ADCs), the investigation of the biological mechanisms of post-translational modifications (PTMs), and the visualization of biomolecular interactions &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;. While numerous strategies have been developed, many suffer from poor yields, limited product stability, demanding experimental procedures, and/or a lack of regioselectivity. Thus, PIC principles have been implemented to address these limitations, leading to the development of PAB strategies which achieve precise, regioselective modification of biomolecules. In this Account, we describe the development of PAB techniques within our group at the University of Cambridge and Instituto de Medicina Molecular (iMM) over the past five years. Our journey with PAB began serendipitously while investigating maleic acid derivatives for cysteine bioconjugation. Here, we discovered the secondary participation of proximal lysines on Trastuzumab-V205C and Gemtuzumab-V205C, conjugatable THIOMAB antibodies commonly used in ADCs, leading to the formation of distinct bioconjugate products relative to IgGs without such lysines. Further investigation into the proximal lysine (K207) of Trastuzumab-V205C revealed that residue 207 could be harnessed directly or mutated to precisely tune the stability of ADCs due to proximity interactions between K207 and covalent modifications of C205. Considering that two Trastuzumab drug conjugates are approved for clinical use, these findings have contributed to the evolving understanding of the chemical landscape of this antibody and help inform future ADC design and development. Further, we describe efforts from our group to develop two distinct PAB approaches: regioselective lysine acetylation of histone H3 and phage display-compatible peptide cyclization. These strategies combine induced-proximity with traditional bioconjugation techniques to enable regioselective modification of biomolecules which are historically difficult to selectively modify. These methods are readily adaptable to related syste","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"42 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141062","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":"Triplet–Triplet Annihilation Upconversion: From Molecules to Materials","authors":"Hong-Juan Feng, Ming-Yu Zhang, Lin-Han Jiang, Ling Huang, Dai-Wen Pang","doi":"10.1021/acs.accounts.5c00403","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00403","url":null,"abstract":"Photon upconversion, particularly triplet–triplet annihilation upconversion (TTA-UC), converts low-energy photons into higher-energy ones through multiphoton fusion, offering unique photophysical properties with broad applications. As a new generation of organic upconversion materials, TTA-UC shows great promise in biosensing, biomedicine, photoredox catalysis, and solar energy harvesting. For example, TTA-UC-based nanoprobes enable highly sensitive, background-free biomarker detection; TTA-UC nanoparticles act as phototransducers that extend optogenetic responses into the near-infrared region; their nonlinear luminescence supports high-resolution 3D printing; and they enhance photon utilization in photovoltaics. Although significant progress has been made in the past decade, challenges remain, including developing high-performance near-infrared TTA-UC pairs with ultralarge anti-Stokes shifts, creating general strategies for synthesizing water-dispersible and oxygen-resistant nanoparticles, and expanding biomedical applications to promote clinical translation.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"80 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077929","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}