ACS Central Science最新文献

A central challenge across modern chemistry, biology,materialsscience, and origins-of-life research is obtaining a balance betweenharnessing beneficial photoreactions and minimizing detrimental photodamage.Here, we have discovered an aggregation-induced photoprotection pathwayprovided by nonconjugated small molecules. Although conventionallyclassified as UV-transparent due to the lack of chromophores, thesemolecules are found to form supramolecular assemblies at elevatedconcentrations and develop emergent UV-absorbing properties, likelyvia slip-stacked J-aggregation, as confirmed by multiple spectroscopiccharacterizations. Density functional theory calculations furtherelucidated the mechanism of the observed concentration-dependent absorption.A predictive structure–property relationship has been proposed.Regulated by concentration, this effect can smartly allow necessaryphotoreactions while shielding critical biomolecules from excessiveUV radiation. It also suggests that self-photoprotection of the aggregatablemolecules could have enabled their prebiotic survival and enduringpresence under harsh UV conditions. Furthermore, these findings promptedus to develop a convenient and noninvasive photoprotection strategyfor contemporary plastic materials using inexpensive and environmentallyfriendly small agents.

The design of epitope-focusedimmunogens that steer serumantibodyresponses toward epitopes targeted by broadly neutralizing antibodies(bnAbs) is a promising approach to develop broad-spectrum vaccinesagainst pathogens with high genetic variability. Here, we introducea strategy called epitope cleavage, which involves “cleaving”an epitope to steer antibodies away from it onto other regions ofan antigen. We demonstrated the utility of epitope cleavage usingtwo independent approaches: circular permutation and proteolytic cleavage.We first designed a sarbecovirus vaccine candidate by circularly permutingthe receptor binding domain (RBD) of the severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2) spike protein; we next designedbroad Ebolavirus immunogens by inserting the TEV protease cleavagesite into the glycan cap of Ebola glycoprotein (GP) for site-specificepitope cleavage. By cleaving variable regions on each antigen, boththe circular permuted RBD and cleaved GPs elicited antibodies withenhanced cross-reactivity to related viruses compared to unmodifiedantigen and exhibited a reduction in antibody responses toward the“cleaved” epitope. Our results present epitope cleavageas a vaccine design strategy that redirects antibody responses withoutcompromising immunogenicity.

Charged water microdroplets that are aerodynamicallyacceleratedupon introduction into an atmospheric sampling mass spectrometer interfacecan undergo glancing collisions that lead to surprising electrochemicalprocesses. A custom charge detection instrument with a 24-elementdetector array is used to determine the outcomes of glancing collisionsof individual charged water microdroplets with stainless-steel surfacesover a well-defined and narrow angle of ∼0.15° ±0.03°. Water droplets entering the high-vacuum region with anglesof <0.11° pass through the detector unimpeded and have kineticenergies in the MeV range depending on droplet size due to aerodynamicacceleration alone. Droplets that have glancing surface collisionsundergo extensive oxidation or reduction through the removal or additionof up to tens of thousands of electrons per collision, independentof their initial charge or polarity, although some ion transfer mayalso play a role. The propensity for these two electrochemical processesappears stochastic, although more highly charged droplets appear toundergo charge reduction more readily. These results clearly demonstratethat highly energetic electrochemical processes of any type can occurwithin charged or uncharged aqueous microdroplets of any polaritythat are introduced into mass spectrometers and may explain the observationof some unusual ions that have been reported in some microdropletreaction studies.

Fibrotic diseasesremain among the most intractable humandisorders,largely due to the absence of therapies capable of directly modulatingthe core cellular programs that drive pathological matrix depositionand tissue remodeling. To address this unmet medical need, we reportan integrated, chemistry-driven discovery platform for function-orientedmolecular design and discovery that combines scaffold redesign ofa classical natural product pharmacophore with human induced pluripotentstem cell (iPSC)-based phenotypic screening to identify potent antifibroticagents. Systematic modification of the artemisinin scaffold led tothe identification of 6-aza-artemisinins with markedly enhanced antifibroticactivity, including an N6–N6′ dimeric analog exhibitinghigh potency at sub-micromolar concentrations. These compounds suppressedcollagen production in systemic sclerosis patient-derived fibroblastsand ameliorated fibrosis in a bleomycin-induced murine model, withsuperior efficacy relative to the clinically used antimalarial drugartesunate. Notably, efficacy was observed even when treatment wasinitiated after fibrosis establishment. Transcriptomic analysis revealedcoordinated suppression of core fibrotic and inflammatory pathways,providing mechanistic insight into the observed therapeutic effects.Collectively, these findings establish 6-aza-artemisinins as a newchemotype for antifibrotic intervention and illustrate how scaffold-levelredesign of natural products, integrated with disease-relevant stem-cell-basedmodels, can enable next-generation function-driven therapeutic discovery.

Rechargeable magnesiumbatteries are promising next-generationenergy storage systems owing to the low cost and high natural abundanceof magnesium. However, their practical application is critically impededby the parasitic decomposition of conventional electrolytes at theMg anode, leading to the formation of a passivation layer, high desolvationbarriers, and poor cycling stability. Herein, triethyl phosphate (TEP)is introduced as a cosolvent into the Mg(OTf)₂ + MgCl₂-DME electrolyte to regulate solvation structures and interfacialchemistry. Comprehensive spectroscopic and electrochemical analysesreveal that TEP facilitates salt dissociation and reconstructs theMg²⁺ solvation structure, thereby reducing the desolvationbarrier and promoting ion transport. Meanwhile, TEP contributes tothe formation of a stable and robust solid electrolyte interphaseon the Mg anode, effectively suppressing side reactions and enablinguniform Mg deposition. The Mg||Mg symmetric cell exhibits stable cyclingfor over 3500 h with an overpotential below 0.2 V at 0.1 mA cm^–2 and 0.05 mAh cm^–2. The Mg||Mo asymmetric cell delivers a Coulombic efficiency of 99.4%after 3000 h at 0.5 mA cm^–2 and 0.25 mAh cm^–2. Furthermore, the Mg||α-MnO₂ fullcell maintains a discharge capacity of 176.9 mAh g^–1 after 350 cycles at 0.1 C. This work provides a solvation-regulationstrategy for designing high-performance Mg electrolytes.

The pathological aggregation of α-synuclein (α-syn),an intrinsically disordered protein that regulates synaptic vesicletrafficking in the brain, is a defining molecular feature in Parkinson’sdisease (PD). Early oligomeric assemblies are widely considered themost neurotoxic species, yet their structural features remain unexploreddue to their low abundance, transient, and fragile nature. Here, weestablish a trapped ion mobility-mass spectrometry (TIMS-MS) strategythat enables direct detection and structural interrogation of theseoligomers. Low-flow size exclusion chromatography provides MS-compatibledesalting and reveals broad ensemble-level differences between freshand aggregated α-syn. Native TIMS-MS measurements uniquely probenumerous higher-order oligomers, thereby revealing a reduced conformationalheterogeneity with increasing oligomer size, supporting a linear β-strand-typeassembly pathway. These findings show that oligomerization drivesa transition from dynamic monomers to increasingly ordered intermediates.This progressive rigidification is relevant to models in which α-synoligomerization alters normal membrane engagement during PD-associatedaggregation.

Over the past two decades, high-performance materialswith aggregation-inducedemission (AIE) characteristics have emerged as indispensable componentsin modern functional materials science. Among them, AIEgens basedon the restriction of the intramolecular rotation (RIR) mechanismhave been thoroughly studied and developed. AIEgens operating viathe restriction of the intramolecular vibration (RIV) mechanism haveemerged as a promising yet underexplored class; however, they remainconstrained by a limited repertoire of molecular scaffolds and poorlydefined design principles. This outlook categorizes reported RIV-typeAIEgens into four types based on a geometry-oriented classificationof molecular deformation modes: structural inversion driven by aromaticity,bending, twisting, and molecular bond vibration. The representativestructures and underlying RIV mechanisms are elaborated in detail,aiming to establish a framework for the rational design and functionalexpansion of next-generation RIV-type AIEgens, with the ultimate goalof broadening their applications in optoelectronics and biomaterials.

Biaryl frameworkscombining axial and multiple central chiralitiesare highly valuable in synthesis and drug discovery. However, simultaneousconstruction of axial and vicinal central chiralities faces severematching/mismatching limitations. Herein, we describe a dual photoredox/nickel-catalyticsystem for desymmetrization of biaryl dialdehydes. By employing abisoxazoline ligand bearing bulky adamantylphenyl side arms, its chiralcavity and distal substituent effects work synergistically to achievehigh stereoselectivity, furnishing homoallylic alcohols with up to>20:1 dr and 99% ee. DFT calculations demonstrate that stereoselectivityis predominantly governed by a complex network of noncovalent interactionsbetween the ligand and substrate.