JACS Au最新文献

The hybridization of single atom sites (SASs) and nanoparticles (NPs) demonstrates enhanced stability under acidic electrochemical environments when compared to their individual components; however, the underlying synergistic mechanisms remain elusive. Here we synthesize a hybrid catalyst featuring electron transfer from Pt₃Fe NPs to high-spin D1-type FeN₄ SASs. The online inductively coupled plasma mass spectrometry technique confirms a mutual suppression of electrochemical dissolution between Pt₃Fe and D1-FeN₄. In situ spectroscopy and theoretical calculations elucidate the mechanisms at play: electron enrichment at the D1-FeN₄ site strengthens the Fe-N bond, thereby elevating the N-hydrogenation energy barrier. Conversely, electron withdrawal reduces the d-band center of Pt, consequently weakening the oxygen adsorption strength and inhibiting the formation of Pt oxides. Owing to mutual dissolution inhibition, the hybrid catalyst retains 99.6% of its oxygen reduction reaction (ORR) mass activity at 0.85 V (versus RHE) following 30,000 accelerated stress test cycles between 0.6 and 1.0 V in an inert atmosphere, markedly surpassing those of single-component counterparts. This work offers critical insights into the intricate synergistic interactions between SASs and NPs, paving the way for the rational design of SASs-NPs hybrid catalysts for ORR or beyond.

Late transition metal aryne complexes are stable, isolable counterparts to free aryne intermediates. However, their utility has largely been limited since the Aryne Distortion Model (ADM) cannot be applied to substituted aryne complex reactivity, leading to nonselective reactions. Our group recently reported the first regioselective synthesis and difunctionalization of a CyPHOX-Ni o-methoxybenzyne complex. However, to increase the utility of these complexes in synthesis, their electronic structure, reactivity, and the impact of aryne substituents on selectivity must be understood. Herein, we report the first comprehensive experimental electronic structure study of aryne complexes, which has been carried out via UV/vis spectroscopy and cyclic voltammetry (CV) with an array of o-substituted arynes. CyPHOX-Ni aryne complexes exhibit a metal-to-ligand charge transfer (MLCT), and this transition as well as their oxidation potentials trend with Hammett parameters for the aryne substituents. To gain further insight into the origins of regioselectivity in CyPHOX-Ni aryne complex formation and difunctionalization, a combination of single-crystal X-ray crystallographic and density functional theory (DFT) structural studies were carried out. Our findings lead us to propose a Metal Aryne Reactivity/Selectivity (MAR/S) Model, which shows that CyPHOX-Ni aryne binding selectivity is governed by a combination of sterics and aryne distortion, whereas selectivity in functionalizations is directed by the phosphine trans influence.

Tryptophan (Trp) displays unique physicochemical properties due to its C3-substituted indole ring, containing a hydrophobic benzene ring and a hydrophilic N-H bond. Herein, we synthetically incorporated five Trp positional isomers with C2/4/5/6/7-substituted indoles in place of the Trp of residue 11 in gramicidin A, a 15-mer linear peptidic natural product. Gramicidin A conducts monovalent cations across the cell membrane and exhibits potent toxicity against both bacterial and mammalian cells. Our functional evaluation of the five analogs revealed that positional isomerism controlled the overall hydrophobicity and biological activities for the first time. Most importantly, we found that the hydrophobicity of the analogs correlated with the potency of mammalian cytotoxicity but not with the strength of the antibacterial activity, indicating that antibacterial and mammalian toxicities can be separated only by tuning the hydrophobicity. In addition, we designed and synthesized a triply mutated analog, in which the original valine, leucine, and Trp were replaced with less hydrophobic threonine, valine, and a C5-isomer, respectively. While the original antibacterial activity was maintained, the mammalian toxicity of the analog was more than 20-fold weaker. Consequently, these new findings offer a novel molecular editing approach to optimize the physicochemical and biological properties of Trp-containing bioactive peptides and proteins.

Structural DNA nanotechnology enables the programmable construction of nano- to microscale assemblies with high resolution, yet predicting their mechanical behavior prior to synthesis remains challenging. In this paper, we introduce SNUPI, a computational framework that predicts the shape and mechanical responses of structured DNA assemblies using finite element-based analysis. SNUPI uses design files from caDNAno and performs static analysis, normal-mode analysis, and Langevin dynamics simulations to evaluate equilibrium configurations, dominant deformation modes, thermal fluctuations, and intercalator-induced effects. We demonstrate that SNUPI can offer an efficient and accessible platform for pre- and postsynthetic evaluation, facilitating rational design and analysis of complex DNA architectures.

The central goal of RNA atomic mutagenesis is to evaluate the presumed contacts between individual atoms and their interaction partners with regard to function. This is made possible, for instance, by deaza-modified nucleobases, which are introduced site-specifically into RNA. Mostly, nucleotides with a single nitrogen-to-carbon exchange have been used so far while double exchanges are largely missing although such modification patterns would be highly useful. Here, a systematic study on 1,3-deazaguanosine (c¹c³G) is reported. We present the first synthesis of this nucleoside and an appropriately protected c¹c³G phosphoramidite for RNA solid-phase synthesis. Comprehensive experimentation on c¹c³G modified RNAs, using UV melting profile analysis together with NMR spectroscopy, shed light on the thermodynamics and base pairing properties. We found that c¹c³G destabilizes RNA double helices, but it can integrate well therein without impairing neighboring base pairs. Our data also show that, although two hydrogen bonds are possible in a c¹c³G - C Watson-Crick base pair geometry, the pairing strength is significantly weaker than that of an A-U pair. This can be explained by a loss of stacking capability when the guanine heterocyclic core is replaced by the shape-complementary benzimidazole analog. This observation has implications for the etiology nucleic acids and may explain why purines have evolved as a dominating heterocyclic component of these fundamental biomacromolecules. Furthermore, our findings help to properly apply c¹c³G in atomic mutagenesis experiments, particularly for probing the transition state of self-cleaving nucleolytic RNA. We demonstrate this for the twister ribozyme by identifying a double contact of a guanine in its active site that impacts catalytic activity by 5 orders of magnitude.

Photodynamic immunotherapy realized with photosensitizers has garnered significant interest in tumor therapy. A complete set of photosensitizer design rules has not been established yet. Herein, the side arms of thio-pentamethine cyanine dye (TCy5) are proven as crucial sites for designing efficient photosensitizers. With precise molecular design, bulky groups on the side arms can shape TCy5 as an efficient photosensitizer compared to TCy5 with alkyl groups. These bulky groups can shape the polymethine chain of TCy5 and regulate the molecular configuration, which narrows the singlet-triplet energy gap and promotes intersystem crossing. Substituting naphthyl groups for alkyl groups increased the singlet oxygen quantum yield of TCy5 from 0 to 41%. Moreover, TCy5 with naphthyl groups efficiently induced immunogenic cell death and activated immune responses in vivo, achieving effective photodynamic immunotherapy. This study serves as a paradigm that the shaping strategy via bulky groups can design efficient photosensitizers for photodynamic immunotherapy.

The quantitative analysis of blood HBV DNA is essential for controlling the spread of HBV and improving the prognosis of individuals infected with the virus. Yet the HBV genome exhibits complex variation, such as multiple-site mutations for entecavir resistance, closely adjacent mutation loci, and the need to distinguish missense from nonsense mutations due to genetic code degeneracy and amino acid mutation conservatism, creating challenges for detection specificity and mutation identification. Herein, this study introduced an AND logic gate-based dual-specificity DNA circuit for HBV DNA detection, integrating toehold-mediated DNA strand displacement and RNase H cleavage through a well-designed probe containing an identification element and an amplification element. By this DNA circuit, we achieved enhanced sensitivity (limit of detection: 29.11 fM) and high specificity to discriminate adjacent single-base mismatches with excellent performance in clinical samples. We envision that this innovative and convenient assay advances point-of-care HBV DNA testing.

Genetically encoded peptide library screening is a powerful strategy for discovering inhibitors of protein-protein and protein-DNA interactions. The Transcription Block Survival (TBS) assay enables the in vivo selection of peptides that antagonize transcription factor (TF) function by linking the inhibition of DNA binding to E. coli survival. However, previous TBS implementations required laborious re-engineering of the mDHFR coding region for each new target, limiting utility. Here, we present an enhanced and streamlined TBS platform that increases throughput, simplifies target switching, and improves selection stringency. By relocating TF DNA-binding sites from within the mDHFR coding sequence into the mDHFR 5'-promoter/untranslated region, we preserve mDHFR folding and function, enabling rapid interchange of TF targets without the need for extensive construct redesign. We validated this system using three distinct TF targets, CREB1, ATF2, and DLX5, and two distinct consensus sites, demonstrating robust transcriptional block upon TF binding and efficient growth rescue upon peptide-mediated antagonism. Importantly, we expand the platform to accommodate full-length TFs, as exemplified by DLX5, allowing selection against biologically relevant full-length, multidomain proteins without immobilization or tags. TBS continues to function exclusively by selecting for the disruption of protein-DNA binding, ensuring mechanistic precision. Using this optimized TBS system, we successfully screened an 11.3-million-member peptide library to identify a potent antagonist of ATF2-CRE DNA binding within three months. This next generation TBS platform significantly improves screening efficiency and selection pressure while maintaining high biological relevance, providing a versatile and scalable tool for discovering functional peptide inhibitors of protein-DNA interactions with therapeutic potential.

Aryltetralin lactones featuring vicinal stereogenic centers at their ring junctions are important scaffolds in pharmacologically relevant cyclolignans. Currently, the direct and efficient assembly of tetracyclic core scaffolds from simple acyclic precursors is challenging. Herein, we developed a conformation-assisted radical-initiated iodocarbocyclization of C-(sp3)-H bonds in 5-alkenylmalonates. This was followed by lactonization for the direct assembly of aryltetralin lactone scaffolds. Nine aryltetralin lactone cyclolignans were successfully produced by unified asymmetric total syntheses. This methodology shows potential for advancing both medicinal chemistry and biological research.

The advancement of cancer immunotherapy has focused on developing therapies that not only target tumor progression but also enhance immune responses, which could potentially shift the balance within the tumor microenvironment (TME) to promote a more immune-competent environment and improve the effectiveness of antitumor immunotherapies. This study evaluates the internalization of single-stranded RNA origami (ssRNAOG) in coculture models mimicking the TME in vitro and the antitumor efficacy of the combination of ssRNAOG with 5-fluorouracil (5-FU) in pancreatic ductal adenocarcinoma (PDAC) models. The internalization of ssRNAOG triggers the TLR3 signaling pathway, leading to robust innate immune activation. Notably, ssRNAOG induces the overexpression of MHC class I protein on macrophages, which recruits NK cells into the TME. The combination of ssRNAOG and 5-FU significantly suppressed tumor cell colony formation in vitro, demonstrating a synergistic antiproliferative effect. Transcriptomic and proteomic analyses revealed a significant upregulation of inflammatory cytokines and the activation of NF-κB and STAT1, which are indicative of M1-like polarization in macrophages. In vivo administration of both ssRNAOG and 5-FU revealed a marked reduction in tumor burden and an extension of survival in mice bearing xenograft PDAC tumors. Immunohistochemistry revealed a shift in macrophage polarization toward the M1-like phenotype, which is associated with enhanced proinflammatory responses and reduced tumor proliferation. These findings indicate that ssRNAOG, as a potent modulator of the TME that can sensitize resistant tumors to chemotherapy, presents a novel immunotherapeutic strategy for PDAC.