The reversible control of molecular structure by light offers a powerful route toward adaptive and out-of-equilibrium chemical systems, yet detailed mechanistic insight across all relevant time scales remains rare. Here, we investigate the complete photoswitching cycle of square-planar PdII acylthiourea complexes using time-resolved spectroscopic techniques to resolve photodynamics from femtoseconds to hours. Upon excitation of the thermodynamically stable cis isomer, rapid intersystem crossing is followed by structural reorganization into a disphenoidal intermediate that evolves into a semi-dissociated species with transient Pd–O bond cleavage. This intermediate enables ligand flexibility and governs product formation, i.e., allowing access to the metastable trans isomer. The system subsequently undergoes a thermal back-reaction to regenerate the cis ground state, completing a reversible switching cycle on the hour timescale. Both forward and reverse processes are highly sensitive to ligand structure and solvent environment, highlighting the role of coordinating solvents in modulating the pathway. By resolving the full reaction cascade over more than fifteen orders of magnitude in time, this work provides a mechanistic framework for reversible photoswitching in transition metal coordination systems and establishes design principles based on coordination lability and solvent effects. Reversible control of molecular structures by light is crucial for developing adaptive chemical systems, yet comprehensive mechanistic insights across all relevant timescales are limited. Here, the authors use time-resolved spectroscopy to elucidate the complete photoswitching cycle of PdII acylthiourea complexes, revealing key intermediates and solvent effects that inform design principles for transition metal coordination systems.
Gas-phase electron diffraction techniques have served as prominent methods for probing the structures of molecules. However, these methods may not be effective in distinguishing structures between molecular isomers due to their limited sensitivity to nonadjacent bond structures and electronic configurations. Laser-induced electron diffraction (LIED) offers a compelling alternative as the yield of the self-imaging electron highly depends on the shape of valence orbitals, thereby creating distinct diffraction patterns for isomers. Here, we present theoretical and experimental evidence demonstrating the capability of LIED to distinguish between n-butane and isobutane. The underlying principle is elucidated through modeling the multiorbital tunnel ionization of the molecules and the subsequent rescattering of the ionized electron with the molecule. Our findings highlight LIED as a powerful technique for identifying molecular isomers and shed light on its potential for simultaneously probing the nuclear and electronic structure of a molecule. Although gas-phase electron diffraction has served as a prominent method for probing molecular structure, it may not be effective in distinguishing structures between molecular isomers. Here, the authors report on laser-induced electron diffraction (LIED) as an alternative approach, showing that it can distinguish between n-butane and isobutane unambiguously due to its sensitivity to both molecular geometry and electronic structure, highlighting its capabilities as a background-free probe for nuclear and electron dynamics in molecules.
DNA-mediated multivalent protein self-assembly requires precise design of single-stranded DNA target pairing regions to achieve efficient DNA oligomer self-assembly. However, intrastrand pairing leading to hairpin structure formation during this process often reduces self-assembly efficiency. In this study, we developed a hairpin-constrained DNA (HC-DNA) sequence optimization approach, which integrates a deep learning-based prediction model for accurate hairpin structure identification and employs an intrastrand mutation mechanism to effectively reduce intrastrand pairing length. Experimental results demonstrate that while maintaining the stability of the target pairing region, HC-DNA markedly reduces the melting temperature of single-stranded hairpins, achieving a substantially greater reduction than approaches without hairpin constraints. Furthermore, DNA tetramer self-assembly experiments demonstrate that HC-DNA-optimized sequences exhibit substantially improved self-assembly efficiency and homogeneity compared with sequences designed without hairpin constraints. Overall, HC-DNA provides an efficient computational design tool for the precise construction of DNA oligomers and multivalent molecular assemblies. Efficient DNA-mediated protein self-assembly is often hindered by hairpin structures formed through intrastrand pairing, reducing assembly efficiency. Here, the authors introduce a hairpin-constrained DNA optimization approach using deep learning to reduce hairpin stability, thereby enhancing self-assembly efficiency and homogeneity.
The deposition of β-amyloid (Aβ) in the brains is considered a key factor in the pathogenesis of Alzheimer’s Diseases (AD), as supported by the link between Aβ mutations and familiar AD (FAD). More than ten Aβ mutations have been identified as causative for FAD, yet the molecular architectures of fibrils formed by most of these mutants remain elusive. In this study, we report the cryo-EM structures of Aβ fibrils formed by the Flemish (A21G) and Italian (E22K) mutants at resolutions of 3.1 - 4.0 Å. Aβ42A21G fibrils exhibit four morphologies comprising two distinct conformations, whereas Aβ42 E22K fibrils display a single morphology with a unique fold stabilized by salt bridges involving Lys22. Despite these structural differences, the oligomeric forms of both mutants are recognized by the natural neuronal Aβ receptor LilrB2. Our findings provide molecular insights into how disease-relevant mutations affect Aβ aggregation, with potential implications for the development of therapeutics and diagnostics for corresponding FAD subtypes. More than ten β-amyloid (Aβ) mutations have been identified as causative for familiar Alzheimer’s Diseases (FAD), however, the molecular architectures of fibrils formed by most of these mutants remain underexplored. Here, the authors report the cryo-EM structures of Aβ fibrils formed by the Flemish (A21G) and Italian (E22K) mutants at resolutions of 3.1-4.0 Å and show that, despite structural differences, the oligomeric forms of both mutants are recognized by the natural neuronal Aβ receptor LilrB2.
Among the many anomalous properties of water, the formation of amorphous ice is one of its most intriguing phenomena. When water vapour is deposited at very low temperatures, it forms an amorphous solid known as amorphous solid water (ASW). Here, we combine X-ray free-electron laser pump-probe diffraction, continuum heat-transfer modelling, and molecular dynamics simulations to investigate the transient thermal response of ASW-films on a platinum substrate. Picosecond laser pulses heat the Pt from 100 K to ~700 K and maintain elevated temperatures for several nanoseconds. Contrary to expectations based on diffusive thermal transport, the hundreds-nanometer-thick ASW layer shows no detectable structural change within tens of nanoseconds. Simulations suggest a mechanism in which a nanometric vapour layer spontaneously forms at the interface, suppressing thermal contact and insulating the ice. The experimental data are consistent with a nanometric (~6 nm) interfacial gap, indicating that the anisotropic scattering originates from a vapour-nucleated interfacial layer. This finding highlights a general non-equilibrium mechanism of interfacial thermal decoupling that may extend beyond the specific ASW-metal system studied here.
Molecular representation learning is a cornerstone of AI-driven chemical discovery. However, most molecular hypergraph models define hyperedges using expert-crafted rules and often overlook three-dimensional molecular geometry. Motivated by the close correspondence between molecular structure and spectroscopy, including nuclear magnetic resonance (NMR), mass spectrometry (MS), ultraviolet-visible (UV-Vis), and infrared (IR) spectroscopy, we abstract spectroscopy-related structural cues into four semantic hyperedge types: atom-type, bond-type, bond-angle-type, and conjugated-system hyperedges. We further integrate molecular geometry into hypergraph construction and propose Geo-Hete-HyperGNN, an equivariant molecular hypergraph neural network that jointly captures molecular geometry, chemical semantics, and higher-order interactions through equivariant message passing, implicit relation regularization, and a Mixture of Molecular Hypergraph Experts (MoMHE) readout. With an equivariant self-supervised pretraining strategy, Geo-Hete-HyperGNN improves transferable molecular representations. Experiments on eight MoleculeNet benchmarks demonstrate consistent gains over prior methods, while additional spectroscopy-oriented evaluation on QM9S-QM9NMR validates the proposed hyperedge semantics for UV-Vis absorption, IR frequency, and NMR chemical shift prediction. These results position Geo-Hete-HyperGNN as a strong framework for hybrid geometric-semantic-higher-order molecular modeling. Molecular representation learning is crucial for AI-driven chemical discovery, yet current models often neglect three-dimensional geometry. Here, the authors introduce Geo-Hete-HyperGNN, an equivariant molecular hypergraph neural network that integrates molecular geometry and spectroscopy-related cues, demonstrating improved performance on MoleculeNet benchmarks and spectroscopy predictions, enhancing transferable molecular representations.
A safe, clean, and cost-effective H2 production system is critically important for developing hydrogen energy. Sodium hypophosphite (NHP) represents a promising hydrogen carrier due to its high stability, low cost, and abundance. NHP can hydrolyse under mild conditions to yield H2 without any gaseous by-products. In this work, we report clean and efficient H2 production at room temperature using CuPd/TiO2 catalytic NHP hydrolysis with the rate of 13.53 mL·min−1 (135.3 mL·min−1·g−1) and 100% NHP conversion within 30 min. The catalyst also exhibits excellent recyclability toward H2 production. The two metals in CuPd/TiO2 exhibit a synergistic effect, Cu can facilitate the activation and dissociation of water, whereas Pd sites accelerate the activation and dehydrogenation of H2PO2−. This work develops a new cost-economic and highly efficient catalytic H2 production system, which is expected to contribute to development of hydrogen economy. Sodium hypophosphite (NHP) represents a promising hydrogen carrier due to its high stability, low cost and abundance, however, its potential as a source for hydrogen production remains underexplored. Here, the authors report a room-temperature, additive-free, hydrogen production system based on NHP and water as carriers and CuPd/TiO2 as a catalyst, with NHP reaching 100% conversion within 30 min and a hydrogen production rate of 135.3 mL·min−1·g−1.
Recent advances in generative artificial intelligence have made in silico molecular design a powerful approach for exploring chemical space toward specific goals. However, despite the need for trial-and-error adjustment of generative strategies and reward formulations, most methods implicitly fix the searchable chemical space, significantly limiting flexibility in practical design. This paper introduces ChemTSv3, an exploration framework with a flexible architecture that accommodates diverse design scenarios for adaptive molecular design. Specifically, molecular representations are unified as nodes, including string-based encodings, molecular graphs, and protein sequences. Molecular generations and editing operations are abstracted as transitions between nodes, allowing graph-based modifications, sequential mutations, and large-language-model-driven transformations to be handled within the same formulation. Representations and transition types can be dynamically switched to adapt the search space to the stage and nature of the design task. Here we show that this flexibility enables efficient exploration across diverse design spaces, from drug-like small molecules to proteins. Recent advances in generative artificial intelligence have enabled in silico molecular design to become a powerful approach for exploring chemical space toward specific design goals across various domains, however, most existing generation methods implicitly fix the searchable chemical space, limiting their flexibility. Here, the authors introduce ChemTSv3, a generalized framework for reward-directed molecular design that modularizes node states and transitions along with rewards and filters, allowing these components to be defined and interchanged as needed, and demonstrate its applicability to small molecules and protein design.
The increasing of molecular complexity must be understood as a planetary phenomenon where prebiotic chemistry and geological settings converge. In this scene, HCN chemistry may have played a crucial role. In this study, we demonstrate that alkaline water aerosols, cyanide, and mineral substrates can lead to the generation of inorganic-organic hybrid materials under laboratory simulation conditions inspired in plausible primitive geological conditions. After a comprehensive characterization of these hybrid systems by microscopy, thermal and spectroscopic techniques was found that the macromolecular architectures of the organic phases were strongly influenced by mineral type and reaction time, while pH variations and redox conditions modified significantly some of the mineral fractions. Our results challenge the conventional view that minerals merely serve as catalysts or redox substrates in prebiotic chemistry. We show that dynamic interactions between inorganic surfaces and the HCN wet chemistry can generate inorganic-organic hybrid materials, revealing new perspectives to be explored under the light of the chemical evolution and space exploration. Although hydrogen cyanide polymerization has been extensively studied, the effect of minerals in the process in the context of prebiotic chemistry remains underexplored. Here, the authors show that alkaline water aerosols, cyanide and mineral substrates can lead to the generation of inorganic-organic hybrid materials under laboratory conditions inspired by plausible primitive geological conditions, challenging the view that minerals merely serve as catalysts or redox substrates in prebiotic chemistry.
Developing corrosion inhibitors with ultrahigh performance and elucidating the atomic-scale mechanisms underlying their corrosion resistance are critical to both engineering and scientific communities. Herein, we report KZnP3O9 crystal and glass corrosion inhibitors for the corrosion protection of carbon steel Q235 in HCl solution. The KZnP3O9 crystal demonstrates superior corrosion resistance over its glass counterpart, featured by a more compact protective corrosion product film with higher time dependence of impedance and lower areal and linear roughness. Molecular dynamics (MD) simulations reveal that the metaphosphate ion has a higher adsorption energy on the Q235 substrate than orthophosphoric acid and pyrophosphoric acid, and the Fe ion is indirectly adsorbed through its interaction with the phosphate ion. Specifically, the KZnP3O9 crystal demonstrates the highest electrochemical impedance (525 Ω·cm2) and corrosion inhibition efficiency (95%) among all inorganic phosphate corrosion inhibitors. This can be attributed to the double-bridging oxygen of a single PO4 tetrahedron for the crystal, which forms an infinite P3O9 chain or ring with a higher adsorption energy, as opposed to the zero- or single-bridging oxygen of each PO4 tetrahedron for the glass, which has isolated PO4 or P2O7 structures with lower adsorption energy. Phosphate glass inhibitors mitigate carbon steel corrosion in acidic media, but whether crystalline phosphate offers superior corrosion inhibition efficiency and the underlying mechanisms remain underexplored. Here, the authors report KZnP3O9 crystal and glass corrosion inhibitors for carbon steel Q235 in HCl solution, showing that the KZnP3O9 crystal demonstrates superior corrosion resistance over its glass counterpart, with metaphosphate ions exhibiting a higher adsorption energy on the Q235 substrate compared to orthophosphoric acid and pyrophosphoric acid, likely due to the formation of P3O9 structures.
1,2-Dihydro-3H-indazol-3-ones (indazolones) are nitrogen-containing heterocycles with broad biological relevance, yet their synthesis often relies on harsh conditions or expensive metal catalysts. Herein, we report a metal-free continuous-flow photochemical protocol that enables rapid access to indazolone cores under mild and sustainable conditions. Direct irradiation of o-nitrobenzyl alcohols in ethanol at 365 nm generates o-nitrosobenzaldehydes in situ, which subsequently undergo condensation-cyclization with primary amines to afford indazolones. UV-visible spectroscopy combined with conceptual DFT analysis suggests that reaction efficiency is governed by wavelength-dependent substrate absorption: weak absorbers generate nitroso intermediates inefficiently, whereas strongly absorbing substrates undergo competitive photodegradation. By matching the irradiation wavelength to the absorption properties of individual substrates, the accessible chemical space can be extended beyond that obtained under fixed-wavelength conditions. Conceptual DFT further rationalizes substituent-dependent electronic effects, clarifying how photophysical and polar reactivity factors jointly control productive indazolone formation. The reaction scalability is assessed with commercial flow reactors.
X-ray magnetic circular dichroism (XMCD) and resonant inelastic X-ray scattering with magnetic circular dichroism (RIXS-MCD) provide unparalleled insights into the electronic and magnetic dynamics of complex materials. However, interpreting their spectra in mixed-valence systems remains challenging due to intricate many-body interactions and enhanced charge fluctuations. In this study, by utilizing the Anderson impurity model with a full consideration of charge transfer (CT), many-body core-valence exchange correlation (CVEC) effects, and Jahn-Teller (JT) distortions, we systematically investigate the XMCD and RIXS-MCD spectra for a prototypical mixed-valence ferromagnet, La0.7Sr0.3MnO3 film. We demonstrate that simple calculation with limited CT effects fails to capture characteristic substructures observed experimentally. In contrast, an adequate treatment of CT and CVEC effects yields a more consistent description of both XMCD and RIXS-MCD spectra, providing practical guidance for the interpretation of dichroic x-ray spectroscopies in mixed-valence transition-metal oxides. Furthermore, we discuss the role of the JT effect in Mn3+ ions in the determination of their spectra. Although X-ray magnetic circular dichroism (XMCD) and resonant inelastic X-ray scattering with magnetic circular dichroism (RIXS-MCD) provide insights into the electronic and magnetic dynamics of complex materials, interpreting spectra from mixed-valence systems is challenging due to the presence of many-body interactions and enhanced charge fluctuations. Here, the authors use an Anderson impurity model that takes into account charge transfer (CT), many-body core-valence exchange correlation (CVEC) effects and Jahn-Teller (JT) distortions, discussing the role of the JT effect in Mn3+ ions in the determination of their spectra and showing that an adequate treatment of charge transfer and many-body core-valence exchange correlation effects yields a more consistent description of both XMCD and RIXS-MCD data.
L-type amino acid transporter 1 (LAT1) delivers amino acids and amino acid-mimicking drugs across blood–brain barrier and is a key underexplored target against cancer. We investigated molecular triggers of LAT1 conformational changes upon ligand binding performing molecular dynamics simulations on LAT1-substrates and one inhibitor. We realized LAT1 conformational change occurs via a two-step expansion-contraction of the mid-section and water flow propels substrate translocation. Expansion allows water flow from the extracellular H6/H10 sub-pocket, facilitating ligand reorientation, while contraction promotes ligand movement toward H8 and water flow toward the intracellular region. For large substrates (cpd1), leaving the H6/H10 sub-pocket toward H10–H3 is coupled to mid-section expansion of the transporter, promoting water flow and ligand reorientation that drive H10 rotation and intracellular passage. Furthermore, benzoxazole tail of JPH203, a clinically investigated LAT1 inhibitor, can rotate downward during expansion phase, arresting LAT1 in the inward-open conformation by displacing unfavorable water molecules. This finding extends JPH203’s original mechanism, showing that it can block LAT1 not only in outward-facing conformation but by stabilizing the inward-open state. L-type amino acid transporter 1 (LAT1) is a promising yet underexplored target against cancer, with current understanding of LAT1 inhibition being largely based on static structures of LAT1–inhibitor complexes. Here, the authors study molecular triggers of LAT1 conformational changes upon ligand binding through molecular dynamics simulations on LAT1-substrates and one inhibitor, JPH203, revealing alterations in hydration dynamics during transport and showing that JPH203 can block LAT1 not only in an outward-facing conformation but by stabilizing the inward-open state.
As organocatalysts and ligands, N-heterocyclic carbenes are pivotal in asymmetric catalysis, yet Type III C1-symmetric chiral N-heterocyclic carbenes remain underexplored despite their potential for superior stereocontrol. Here, we develop a family of C1-symmetric chiral N-heterocyclic carbene precursors based on the 1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline scaffold in high yields with excellent stereoselectivities (up to 92% yield, >20:1 dr, 99% ee). The synthesis was accomplished through a silver-catalyzed asymmetric [3 + 2] cycloaddition of isocyanoacetates with cyclic azomethine ylides, followed by direct alkylation of the cycloadducts without intermediate isolation. A mechanistic model consistent with experimental observations has also been proposed. This one-pot, two-step protocol is operationally simple, using a concise synthetic route with air- and moisture-stable catalysis and showing high functional group tolerance, with multiple modifiable sites and structural versatility. The utility of these synthesized dihydroimidazolium salts as precursors to chiral N-heterocyclic carbene ligands has been experimentally validated in the Cu-catalyzed asymmetric conjugate borylation of α,β-unsaturated esters followed by oxidation. N-heterocyclic carbenes (NHCs) are pivotal in asymmetric catalysis yet Type III C1-symmetric chiral NHCs remain underexplored despite their potential for superior stereocontrol. Here, the authors develop a family of C1-symmetric chiral compounds based on the 1,5,6,10b-tetrahydroimidazo[5,1-a]isoquinoline scaffold and demonstrate their utility as precursors to chiral NHC ligands.
Halogenation is a widely used strategy, both in nature and medicinal chemistry, to modulate the properties of small molecules. Cyanobacteria are a rich source of halogenases that act regio- and stereoselectively on sp3-hybridized carbon centers, which have been reported to catalyze the incorporation of one or two halogen atoms into each substrate molecule. In this work, we report trichlorinated natural products – lebomboamides – from the cyanobacterium Nostoc sp. LEGE 12454. Lebomboamide A (1) was isolated and characterized by NMR spectroscopy. The three chlorine substituents were found to be located in a γ-chloro,δ-gem-dichloro acyl moiety. A candidate biosynthetic gene cluster (BGC) for lebomboamides (lbb) was identified, encoding a single non-heme Fe(II)/α-ketoglutarate-dependent halogenase (LbbB). In vitro assays demonstrated that this halogenase can perform the triple halogenation of fatty acyl moieties. LbbB is the first reported enzyme capable of performing triple halogenation of sp3-hybridized carbons. We additionally found that enzymes closely related to LbbB, including the previously characterized dichlorinase HctB, can also carry out triple halogenation in vitro, suggesting that this group of halogenases can be fine-tuned for different catalytic outcomes. Halogenation is crucial in modulating small molecule properties, yet enzymes capable of triple halogenation remain elusive. Here, the authors identify a halogenase from the cyanobacterium Nostoc sp. LEGE 12454 capable of triple halogenation on sp3-hybridized carbons.
Protein aggregation is a hallmark of neurodegenerative diseases, where misfolded proteins accumulate into insoluble deposits. Emerging studies indicate that liquid-liquid phase separation (LLPS) may serve as a transient stage in the transition from monomers to amyloid fibrils for several proteins implicated in neurological disorders. In this study, we investigated the interplay between tau and off-pathway oligomers of amyloid-beta (Aβ), the two key proteins in Alzheimer's disease (AD). Our findings demonstrate that tau condensates act as reservoirs for Aβ oligomers under LLPS conditions. Inside the tau condensates, Aβ oligomers reduced tau dynamics and formed discrete puncta, indicating a conducive environment for Aβ oligomer clustering. In contrast, in the absence of LLPS conditions, tau and Aβ oligomers formed solid-like co-aggregates with distinct morphologies. Tau significantly affected the kinetics of Aβ assembly, stabilizing off-pathway oligomers and inhibiting their replacement by amyloid fibrils. Our results highlight interactions between higher-order assemblies of tau and Aβ that may contribute to AD pathology.
Photodynamic therapy (PDT) is a promising treatment that uses reactive oxygen species (ROS) generated by light-irradiated photosensitizers (PSs) in the presence of molecular oxygen (O₂). However, its efficiency is heavily compromised in aqueous environments and living systems. Here, we report a series of self-assembled Ir(III) complex-based PSs based on a targetable diphenylalanine-derivative peptide assembly strategy. The complexes (1 − 3) form spherical nanoparticles (NPs), with complexes 2 and 3 exhibiting aggregation-induced emission (AIE) characteristics in water, and strong type I/II mixed PDT in aqueous solution. With the assistance of a tumor-targeting biotin fragment, these complexes could target TNBC cells with precise phototoxicity at a low dose (IC50 = 0.127 μM), low irradiation power (30 mW cm−2), and short exposure time (2 min). Moreover, complexes 1 and 2 can induce cuproptosis without copper ion loading, amplifying its anticancer activity. This is the first example of luminescent metal complexes that can trigger cuproptosis without copper supplementation. Photodynamic therapy (PDT) faces challenges in aqueous environments and living systems due to compromised efficiency. Here, the authors develop self-assembled Ir(III) complex-based photosensitizers that form nanoparticles with aggregation-induced emission, enabling precise phototoxicity against TNBC cells and inducing cuproptosis without copper loading.
Submarine alkaline hydrothermal vents (SAVs) are geological structures considered plausible sites for life emergence, here a life-like thermodynamic disequilibrium is generated by the presence of two fluids with different pH and composition across opposite surfaces of a mineral membrane. The redox potential generated can drive the formation of organic molecules by coupling CO2 reduction with H2 oxidation. In this work, we propose a novel electrochemical model for SAVs, treating them as short-circuited fuel cells. Using two iron sulfide electrodes exposed to the different environments, we measured the potential difference (Uc) generated in the cell by the pH and redox gradients, namely the open circuit potential difference between two electrodes. Short-circuiting the electrodes equalized their potential, i.e. the mixed potential (Em) and allowed a current to flow and thus two or more redox reactions to proceed. Under far-from-equilibrium conditions, spontaneous current generation was observed for the first time ever, leading to the formation of formic acid. Our results show the active role of the mineral barrier as the site where geochemical energy is dissipated and converted into the very first protobiotic chemistry. Submarine hydrothermal vents are among the most compelling candidates for where life on Earth began, their mineral walls dissipate the redox and pH gradients to drive primitive chemistry. Here, researchers introduce an electrochemistry-grounded model that treats these vents as a short-circuited fuel cell, building iron sulfide electrodes to capture spontaneous potential and current generation in real time — and catch CO2 being converted into formic acid, an early building block of life.
Abstract Viral proteases represent validated targets for direct-acting antivirals and the treatment of associated infections. In co-crystal structures of M pro of SARS-CoV-2 with peptidomimetic inhibitors, we noticed a spatial proximity of sidechains filling the S1’ and S2 pockets, as well as those filling S3 and S1 pockets. To enhance molecular rigidity, the proximal residues were conformationally fixed by macrocyclization. We report the synthesis of two macrocyclic series, i.e. exocyclic nitriles with linked P3 and P1 residues and endocyclic α-ketoamides with linked P1’ and P2 residues, and characterize their binding modes and bioactivities. The 17-membered macrocyclic α-ketoamide 20 f inhibited M pro (IC₅₀ = 370 nM) and exerted anti-SARS-CoV-2 effects (EC₅₀ = 1.9 μM). Leveraging structural similarities between M pro and the 3C pro of enterovirus D68, we describe with two co-crystal structures how α-ketoamide macrocycles bound to and inhibited the enteroviral protease. Notably, 20 f exhibited very potent antiviral activities with EC₅₀‘s of 33, 133, and 146 nM against EV-D68, EV-A71, and CVB3, respectively. The study demonstrates how broad-spectrum activity can be achieved with direct-acting antivirals.
In operando Raman investigations of iridium-based oxygen evolution (OER) catalysts in water electrolysis offer insights into catalytically relevant species and pathways, enabling optimization towards effective use of iridium. This work builds upon existing academic studies by utilizing industrially relevant proton exchange membrane catalyst-coated membrane electrode assemblies in an applicable cell design. To overcome challenges in spectral analysis, a methodology for spectral deconvolution with a focus on stability and validity was developed and verified by two-dimensional correlation analysis. Based on in operando studies during potential-dependent electrolysis and catalyst relaxation at open circuit potential, the oxygen evolution reaction pathway on iridium-based catalyst-coated membrane electrode assemblies was found to involve a concerted redox reaction of both iridium and oxygen. Formation of the active species occurs from iridium oxo-hydroxides and crystalline IrO2 via oxidative charging. Enhanced proton conduction due to ionomer presence in application-oriented systems promotes deprotonation, causing oxidative charging of the catalyst well before the oxygen evolution reaction onset.
