ACS Publications最新文献

{"title":"Azapeptide-Based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination, and Antiviral Activity.","authors":"Philipp Flury, Jyoti Vishwakarma, Katharina Sylvester, Nobuyo Higashi-Kuwata, Agnieszka K Dabrowska, Renee Delgado, Ashley Cuell, Rahul Basu, Alexander B Taylor, Ellen Gonçalves de Oliveira, Mateus Sá Magalhães Serafim, Jingxin Qiao, Yan Chen, Shengyong Yang, Anthony J O'Donoghue, Hiroaki Mitsuya, Michael Gütschow, Stefan A Laufer, Christa E Müller, Reuben S Harris, Thanigaimalai Pillaiyar","doi":"10.1021/acs.jmedchem.5c01520","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01520","url":null,"abstract":"<p><p>M^pro of SARS-CoV-2 plays a vital role in the replication and pathogenesis of virus. Additionally, its high conservation within the <i>Coronaviridae</i> family makes it an attractive therapeutic target for developing broad-spectrum agents. This study describes the design, synthesis, and structure-activity relationships of azapeptide-based SARS-CoV-2 M^pro inhibitors, leading to several compounds with nanomolar IC₅₀ values. Examples include <b>14r</b> (IC₅₀ = 13.3 nM), <b>14s</b> (IC₅₀ = 30.6 nM), <b>20a</b> (<b>TPG-20a</b>, IC₅₀ = 28.0 nM), and <b>20g</b> (IC₅₀ = 30.4 nM). Some compounds inhibit MERS-CoV and SARS-CoV-1 M^pro but not the human protease cathepsin L. Several inhibitors, such as <b>20a</b> and <b>20f</b>, exhibit antiviral activity with potencies comparable to nirmatrelvir and activity against the E166V-carrying SARS-CoV-2 variant (SARS-CoV-2^E166V). An M^pro cocrystal structure with <b>20a</b> shows a covalent adduct with the catalytic Cys145. Overall, these new inhibitors are promising chemical tools that may contribute to the identification of future pan-anticoronaviral drugs.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crossed-Beams and Theoretical Studies of the Multichannel Reaction O(³P) + 1,2-Butadiene (Methylallene): Product Branching Fractions and Role of Intersystem Crossing.","authors":"Gianmarco Vanuzzo, Andrea Giustini, Adriana Caracciolo, Silvia Tanteri, Domenico Stranges, Marzio Rosi, Piergiorgio Casavecchia, Nadia Balucani, Maristella Di Teodoro, Sarah Nicole Elliott, Carlo Cavallotti","doi":"10.1021/acs.jpca.5c03937","DOIUrl":"10.1021/acs.jpca.5c03937","url":null,"abstract":"<p><p>The reactions of ground state oxygen atoms, O(³P), with unsaturated hydrocarbons (UHs) are relevant in the oxidation in different environments. They are usually multichannel reactions that exhibit a variety of competing product channels, some of which occur adiabatically on the entrance triplet potential energy surface (PES), while others occur nonadiabatically on the singlet PES that can be accessed via <i>intersystem crossing</i> (ISC). ISC plays a key role on the mechanism of these reactions, impacting greatly the product yields. Identification of all primary reaction products, determination of their branching fractions (BFs), and assessment of the role of ISC is central for understanding the mechanism of these reactions. This goal can be best achieved combining crossed-molecular-beam (CMB) experiments with universal, <i>soft</i> ionization, mass-spectrometric detection and time-of-flight analysis to high-level <i>ab initio</i> electronic structure calculations of triplet/singlet PESs and Rice-Ramsperger-Kassel-Marcus/Master Equation (RRKM/ME) computations of product BFs with inclusion of ISC effects. Over the years this combined approach was found to be rewarding and successful for O(³P) reactions with the simplest alkynes, alkenes, and dienes containing two, three, or four carbon atoms. Here, we report the full experimental and theoretical work on the reaction O(³P) + 1,2-butadiene that permits us to explore how the mechanism and product distribution vary when moving from O(³P) + allene (propadiene) to O(³P) + methylallene (1,2-butadiene) and when comparing this system to related C4 unsaturated systems, namely O(³P) + 1-butene and O(³P) + 1,3-butadiene. In the present CMB experiments at the collision energy of 41.8 kJ/mol we have observed and characterized nine different product channels. Synergistic <i>ab initio</i> transition-state theory-based master equation simulations coupled with nonadiabatic transition-state theory on the coupled triplet/singlet PESs were used for computing the product BFs and assisting the interpretation of the experimental results. Theoretical predictions and experimental results were found to be in overall good agreement. The finding of this work can be useful for the kinetic modeling of the oxidation of 1,2-butadiene and of systems involving 1,2-butadiene as an important intermediate.</p>","PeriodicalId":59,"journal":{"name":"The Journal of Physical Chemistry A","volume":" ","pages":"8278-8302"},"PeriodicalIF":2.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical Role of Mg²⁺ Ions in RNA Folding Transitions: Anchoring the A-Minor Twist in the SAM-II Riboswitch.","authors":"Rafael G Viegas, Anushree Sinha, Avijit Mainan, Karissa Y Sanbonmatsu, José N Onuchic, Susmita Roy, Vitor B P Leite","doi":"10.1021/acs.jpcb.5c02586","DOIUrl":"10.1021/acs.jpcb.5c02586","url":null,"abstract":"<p><p>Magnesium ions (Mg²⁺) play a crucial role in stabilizing various RNA tertiary motifs, such as pseudoknots, G-quadruplexes, kissing loops, and A-minor motifs, to name a few. Despite their importance, the precise location and role of Mg²⁺ ions in RNA folding are challenging to characterize both experimentally and computationally. In this study, we employ an all-atom structure-based model integrated with the dynamic counterion condensation (DCC) model to investigate the folding and unfolding transitions of apo SAM-II riboswitch RNA at physiological concentrations of Mg²⁺. Using the Energy Landscape Visualization Method (ELViM), we trace the transitions between conformational phases, focusing on magnesium interactions. ELViM reveals key structural ensembles during the transition from the unfolded to the folded state, facilitated by a partially folded intermediate, which is conformationally similar to that found in early ¹³C-CEST NMR. Interestingly, this study finds the rate-limiting transition from the unfolded state to this intermediate initiated by the formation of an A-minor twist interaction, a stable scaffold in the aptamer domain, stabilized by specific Mg²⁺ coordination. The contact probability map shows that this specific Mg²⁺ bridges a helical region and an internal loop, mitigating electrostatic repulsion at the phosphate level. As a result, a set of hydrogen-bond-mediated interactions between the loop and the minor groove of the helix is stabilized, supporting the formation of the A-minor twist. This study underscores the critical role of Mg²⁺ in driving the rate-limiting event of RNA folding and highlights its strategic location in stabilizing the A-minor twist motif, essential for the global packing and regulatory function of the SAM-II riboswitch aptamer.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"9058-9067"},"PeriodicalIF":2.9,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Correlating Carrier Localization to Optoelectronic Behavior of Monolayer MoS₂\".","authors":"Arup Singha, Aparna Parappurath, Agniva Paul, Sanjitha K Shetty, Kenji Watanabe, Takashi Taniguchi, Arindam Ghosh, Sreemanta Mitra","doi":"10.1021/acsami.5c17397","DOIUrl":"https://doi.org/10.1021/acsami.5c17397","url":null,"abstract":"","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Hydration on the α-Helical Structure of S-Peptide in RNase-S.","authors":"Nayana Edavan Chathoth, Revanth Elangovan, Padmesh Anjukandi","doi":"10.1021/acs.jpcb.5c00938","DOIUrl":"10.1021/acs.jpcb.5c00938","url":null,"abstract":"<p><p>The folded conformation of a protein is essential for its enzymatic function, as it provides the structural framework required for substrate recognition, active site organization, stability, conformational flexibility, catalytic activity, and regulatory control. Ribonucleases (RNases) play a critical role in biological systems by catalyzing the degradation of RNA into smaller fragments. RNase-S is a heterodimeric protein composed of two subunits: the S-Peptide and the S-Protein. The S-Peptide serves as the catalytic component, enabling ribonuclease activity, while the S-Protein maintains the structural integrity of the enzyme. The proper folding of the S-Peptide in RNase-S is vital for enzymatic function, as it ensures the formation of the active site, facilitates substrate recognition and binding, maintains structural stability and flexibility, and enables efficient catalysis. Any disruption in its folded conformation can compromise enzymatic activity and hinder RNA cleavage. From classical molecular dynamics and constant-force MD simulations, we find that the S-Peptide is significantly more stable in complex with the S-Protein than in its isolated form. This increased stability is due to differences in hydration levels, which help preserve its intramolecular noncovalent interactions. Our findings also reveal that the S-Peptide binds to the S-Protein through an induced fit mechanism rather than conformational selection.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"9043-9050"},"PeriodicalIF":2.9,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coalescence-Induced Growth Doping in a II-VI Magic Size Cluster.","authors":"Hyunggu Kim, Kevin R Kittilstved","doi":"10.1021/acs.jpca.5c04100","DOIUrl":"10.1021/acs.jpca.5c04100","url":null,"abstract":"<p><p>The versatility and stability of semiconductor magic size clusters (MSCs) have been exploited to synthesize unique nanostructures with well-controlled dimensionality. Strategies to incorporate dopant ions such as transition metals into II-VI MSCs typically result in substitutional doping at surface sites. In this study, we investigate the speciation of Co²⁺ in ZnS MSCs using three different cation exchange reactions at moderate temperatures. Using electronic absorption spectroscopy and ligand field theory, we confirm in every scenario that Co²⁺ either substitutes at the surface, remains as a precursor in solution, or forms a Co-rich impurity. However, upon growth of the Co²⁺-doped ZnS MSCs at higher temperatures, we observe conversion of the surface Co²⁺ to internal sites. This observation is consistent with tetrahedral Co²⁺ coordinated to μ₄-S^2- based on comparison of the same transition observed previously with internally doped Co²⁺:ZnS QDs. We propose the internalization is due to a coalescence growth mechanism involving direct attachment, interface relaxation, and reshaping of the Co²⁺-doped ZnS MSCs in contrast to typically observed stepwise MSC growth or Ostwald ripening in doped QDs.</p>","PeriodicalId":59,"journal":{"name":"The Journal of Physical Chemistry A","volume":" ","pages":"8324-8336"},"PeriodicalIF":2.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examining the Effect of an Anion-Binding Reagent on the Structure of Deprotonated Leucine Enkephalin Using Cryogenic-Ion Infrared Action Spectroscopy.","authors":"Madeline Schultz, Nwanne D Banor, Katja Ober, America Y Torres-Boy, Maleesha T Fernando, Miyuru M Wellalage, Neil A Ellis, Gert von Helden, Daniel A Thomas","doi":"10.1021/acs.jpca.5c03984","DOIUrl":"10.1021/acs.jpca.5c03984","url":null,"abstract":"<p><p>Biomolecular systems feature a complex interaction network comprising numerous intra- and intermolecular interactions. By isolating biomolecules under vacuum conditions, the intricate balance between specific interaction motifs can be characterized with precise control over conditions. In this study, we apply cryogenic-ion infrared action spectroscopy and electronic structure methods to examine the structural changes in the deprotonated form of the model peptide leucine enkephalin (YGGFL) upon complexation with diserinol isophthalamide (DIP), an anion-binding reagent. The low-energy conformer of the uncomplexed, deprotonated peptide ([YGGFL - H]^-) adopts a noncanonical turn structure stabilized by intramolecular ionic hydrogen bonding to the C-terminal carboxylate moiety. Despite the favorability of DIP to strongly coordinate with carboxylate residues, we find that the structure of the peptide is largely unaffected by the binding of DIP. Instead, DIP only partially coordinates with the carboxylate moiety and is positioned below the backbone turn of YGGFL to engage in additional hydrogen bonding interactions. These findings underscore the stability of the turn structure and the strong energetic penalty imposed by disruption of this motif even when strong intermolecular coordination is expected.</p>","PeriodicalId":59,"journal":{"name":"The Journal of Physical Chemistry A","volume":" ","pages":"8303-8311"},"PeriodicalIF":2.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Capacitance Spectroscopy for Real-Time Monitoring of RNA Amplification.","authors":"Steffane Q Nascimento, Rodrigo M Iost, Thiago C Oliveira, Erika R Manuli, Geovana M Pereira, Ester C Sabino, Frank N Crespilho","doi":"10.1021/acs.jpcb.5c01815","DOIUrl":"10.1021/acs.jpcb.5c01815","url":null,"abstract":"<p><p>RNA amplification is central to viral diagnostics, yet current optical and fluorometric methods, such as PCR and RT-qPCR, remain costly, complex, and resource-intensive. Here, we introduce differential capacitance spectroscopy (DCS) as a real-time electrochemical method for RNA detection using loop-mediated isothermal amplification. By applying sinusoidal currents to flexible carbon fiber electrodes (0.05 cm², 1 mm apart), DCS monitors changes in electrode-electrolyte interface capacitance, generating a unique arm-shoulder diagram (ASD) for RNA amplification. The ASD reveals exponential and polynomial capacitance variations, distinguishing amplified RNA under isothermal conditions. Our method eliminates the need for sophisticated instrumentation and reduces diagnostic costs while enabling rapid, high-sensitivity detection. Validated with COVID-19 patient samples, DCS provides a promising platform for affordable, scalable, and real-time RNA-based diagnostics, positioning itself as a transformative tool for disease surveillance and clinical applications.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"9051-9057"},"PeriodicalIF":2.9,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Mechanism and Kinetics of Hydroxyl Radical Polymerization of Nonionized Acrylic Acid and Its Derivatives in Aqueous Solution.","authors":"Truong Le Bich Tram, Mai Van Bay, Nguyen Thi Hoa, Adam Mechler, Quan V Vo","doi":"10.1021/acs.jpca.5c04179","DOIUrl":"10.1021/acs.jpca.5c04179","url":null,"abstract":"<p><p>In the free-radical polymerization of acrylic acid derivatives (<b>AAD</b>), including acrylic acid (<b>AA</b>), methyl acrylate (<b>MA</b>), acrylamide (<b>AM</b>), methacrylic acid (<b>MAA</b>), and methyl methacrylate (<b>MMA</b>), initiation and propagation occur via radical addition to <b>AAD</b>. Although extensive experimental data exist about this industrial process, many mechanistic aspects of the reactions themselves remain unclear, largely because of the challenge that the characterization of reaction mechanisms poses to experimental methodology. Computational methods offer an alternative avenue to deliver fast and accurate results on the mechanistic details, as evidenced by various theoretical studies in the literature. Here, we report on quantum chemical computations of the radical polymerization of <b>AAD</b> initiated by the HO^• radical in an aqueous environment (that is used regularly in the polymerization of these species) across a temperature range of 273-373 K. It was determined that the computed rate constants for HO^•-initiated AAD reactions, ranging from 7.95 × 10⁸ to 3.17 × 10⁹ M^-1 s^-1, show strong agreement with experimental values further confirming the accuracy of the method. The calculated propagation rates of <b>AAD</b> range from 1.40 × 10³ to 3.90 × 10⁵ M^-1 s^-1 and also closely align with experimental findings. In terms of the mechanism, the propagation reaction occurs predominantly at the C3 position of the double bond, resulting in polymers containing COOH, CONH₂, or COMe groups situated on each side of the polymeric backbone. The propagation rate increases with temperature within the studied range of 273-373 K.</p>","PeriodicalId":59,"journal":{"name":"The Journal of Physical Chemistry A","volume":" ","pages":"8337-8345"},"PeriodicalIF":2.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surface Engineering by Micropatterned Polymer Brushes: Strategies to Construct and Their Applications in Biomedical Areas.","authors":"Meenakshi Verma, Shubham Roy, Sampa Saha","doi":"10.1021/acsabm.5c01387","DOIUrl":"https://doi.org/10.1021/acsabm.5c01387","url":null,"abstract":"<p><p>Micropatterned polymer brushes are a revolutionary platform that has opened up unique biomedical application possibilities through spatial control of surface characteristics. Unlike traditional polymer-brush coatings that enable homogeneous surface modifications, micropatterned brushes allow the fabrication of heterogeneous surfaces by providing localized functionality for enhanced biological interactions. This review presents different lithography techniques followed by surface-initiated polymerization as advanced fabrication methods that are vital in creating such a modulated surface architecture. Despite remarkable achievements, issues of scalability and reproducibility of the created surfaces remain a core challenge toward their industrial utilization. By critically evaluating these methodologies and their integration with biomedical technologies, we have outlined the current limitations and potential breakthroughs required for the future deployment of micropatterned polymer brushes in healthcare, particularly in areas such as biosensing, drug delivery, and tissue engineering.</p>","PeriodicalId":2,"journal":{"name":"ACS Applied Bio Materials","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}