ACS Chemical Biology最新文献

Revealing the synergistic catalytic mechanism involving multiple active centers is crucial for understanding multiphase catalysis. However, the complex structures of catalysts and interfacial environments pose a challenge in thoroughly exploring the experimental evidence. This study reports the utilization of a CuNi dual-atom catalyst (Cu/Ni–NC) for the electrochemical reduction of CO₂. It demonstrates a high Faradaic efficiency of CO exceeding 99%, remarkable reaction activity with a partial current density surpassing –300 mA cm^–2, and prolonged stability for more than 5 days at a current density of –200 mA·cm^–2. Operando characterization techniques and density functional theory calculations reveal that Ni atoms function as active sites for the activation and hydrogenation of CO₂, while Cu atoms serve as active sites for the dissociation of H₂O, supplying protons for the subsequent hydrogenation process. Moreover, the electronic interactions between Ni and Cu atoms facilitate the formation of *COOH and the dissociation of H₂O, illustrating a synergistic reduction of CO₂ at the dual-atom sites.

Split-intein circular ligation of proteins and peptides (SICLOPPS) is a method for generating intracellular libraries of cyclic peptides that has yielded several first-in-class inhibitors. Here, we detail a revised high-content, high-throughput SICLOPPS screening protocol that utilizes next-generation sequencing, biopanning, and computational tools to identify hits against a given protein-protein interaction. We used this platform for the identification of inhibitors of the HIF-1α/HIF-1β protein-protein interaction. The revised platform resulted in a significantly higher positive hit rate than that previously reported for SICLOPPS screens, and the identified cyclic peptides were more active in vitro and in cells than our previously reported inhibitors. The platform detailed here may be used for the identification of inhibitors of a wide range of other targets.

Ce_0.5Zr_0.5O_2–x (CZO) is widely used for the storage and reaction of O atoms (O*) in chemical looping and emissions control. Reductants react with O* to form vacancies (*) at rates limited by surface reactions with O*, replenished through fast diffusion through CZO crystals. The dynamics and mechanism of these surface reactions remain unresolved because O* stability and reactivity depend very strongly on the extent of CZO reduction during stoichiometric reactions. These thermodynamic nonidealities are evident from free energy penalties in removing O* that increase sharply as intracrystalline O* concentrations decrease, leading to reduction rates that deviate from the expected linear dependence of rates on O* concentrations. Rates of CZO reduction by CO, at conditions resembling “cold start” of vehicle emissions systems, decrease 10-fold when O* concentrations decrease by only a factor of 2; this nonlinearity reflects the strong effects of thermodynamic nonidealities on reaction dynamics. This study addresses and resolves these mechanistic and practical matters using transition state theory, a thermodynamic construct that rigorously accounts for the prevalent nonideal behavior. Such formalisms treat Ce_0.5Zr_0.5O₂ as an ideal solution and O*, *, surface-bound intermediates, and transition states as solutes within a well-mixed Ce_0.5Zr_0.5O_2–x solution with excess free energies that depend strongly on extent of reduction. The nonideal behavior of these solutes and the reactivity of O* in reactions with CO are related to the measured thermodynamics of O* through scaling relations, and the requisite kinetic parameters for the ideal system are independently derived from a mechanism-based interpretation of catalytic CO–O₂ reactions on stoichiometric CZO. These approaches and constructs lead to a kinetic model that accurately describes measured transient stoichiometric reduction rates, but only when incorporated into reaction-convection equations that rigorously capture how the thermodynamic activities of kinetically relevant reactants, transition states, and spectators evolve in time and space. These formalisms provide a general framework for the analysis of stoichiometric processes in strongly nonideal systems that are ubiquitous in carbon capture, energy storage, and environmental remediation.

The dissociation and spillover process of hydrogen is one of the key processes in hydrogenation reactions, but this process is very challenging or even impossible in the presence of a S atom, as S atoms can severely poison the surface of supported metal catalysts. Herein, we report that the efficient dissociation and transfer of hydrogen can be achieved in the presence of S poisoning over the synergetic process of hydrogen transfer units together with H₂ dissociation units in the hydrogenation of 5-nitrobenzothiazole catalyzed by Pt/MoO₃. Pt/MoO₃ showcases 99% conversion with ∼99% selectivity under mild reaction conditions and is one of the most active catalysts reported so far for the hydrogenation of sulfur atom-containing compounds. Mechanism studies, in situ characterization, and density functional theory calculations collectively demonstrate that the MoO₃ support, with H_1.68MoO₃ as an intermediate, acts as a bridge for transferring H species between Pt sites and nitrobenzothiazole. The unique H proton storage and release properties of in situ formed H_1.68MoO₃ not only accelerate the breaking of the N–O bond for the hydrogenation of 5-nitrobenzothiazole but also prevent sulfur poisoning. This work provides a promising strategy to tackle the current challenges in the catalytic hydrogenation of sulfur atom-containing compounds.

Among bacteria used as anticancer vaccines, attenuated Listeria monocytogenes (Lm^at) stands out, because it spreads from one infected cancer cell to the next, induces a strong adaptive immune response, and is suitable for repeated injection cycles. Here, we use click chemistry to functionalize the Lm^at cell wall and turn the bacterium into an "intelligent carrier" of the chemotherapeutic drug doxorubicin. Doxorubicin-loaded Lm^at retains most of its biological properties and, compared to the control fluorophore-functionalized bacteria, shows enhanced cytotoxicity against melanoma cells both in vitro and in a xenograft model in zebrafish. Our results show that drugs can be covalently loaded on the Lm^at cell wall and pave the way to the development of new two-in-one therapeutic approaches combining immunotherapy with chemotherapy.

The electrochemical reduction of nitrate ions to valuable ammonia enables the recovery of nitrate pollutants from industrial wastewater, thereby synchronously balancing the nitrogen cycle and achieving NH₃ production. However, the currently reported electrocatalysts still suffer from the low NH₃ yield rate, NH₃ Faradaic inefficiency, and NH₃ partial current density. Herein, a strategy based on the regulation of the d-band center by Ru doping is presented to boost ammonia production. Theoretical calculations unravel that the Ru dopant in Ni metal–organic framework shifts the d-band center of the neighboring Ni sites upward, optimizing the adsorption strength of the N-intermediates, resulting in greatly enhanced nitrate reduction reaction performance. The synthesized Ru-doped Ni metal–organic framework rod array electrode delivers a NH₃ yield rate of 1.31 mmol h^–1 cm^–2 and NH₃ Faradaic efficiency of 91.5% at −0.6 V versus reversible hydrogen electrode, as well as good cycling stability. In view of the multielectron transfer in nitrate reduction and electrocatalytic activity, the Zn-NO₃^– battery is assembled by this electrode and Zn anode, which delivers a high open-circuit voltage of 1.421 V and the maximum output power density of 4.99 mW cm^–2, demonstrating potential application value.

Deciphering the functional relevance of every protein is crucial to developing a better (patho)physiological understanding of human biology. The discovery and use of quality chemical probes propel exciting developments for developing drugs in therapeutic areas with unmet clinical needs. Myosin light-chain kinase (MLCK) serves as a possible therapeutic target in a plethora of diseases, including inflammatory diseases, cancer, etc. Recent years have seen a substantial increase in interest in exploring MLCK biology. However, there is only one widely used MLCK modulator, namely, ML-7, that too with a narrow working concentration window and high toxicity profile leading to limited insights. Herein, we report the identification of a potent and highly selective chemical probe, Myokinasib-II, from the synthesis and structure-activity relationship studies of a focused indotropane-based compound collection. Notably, it is structurally distinct from ML-7 and hence meets the need for an alternative inhibitor to study MLCK biology as per the recommended best practices. Moreover, our extensive benchmarking studies demonstrate that Myokinasib-II displays better potency, better selectivity profile, and no nonspecific interference in relevant assays as compared to other known MLCK inhibitors.

Tumor-selective degradation of target proteins has the potential to offer superior therapeutic benefits with maximized therapeutic windows and minimized off-target effects. However, the development of effective lysosome-targeted degradation platforms for achieving selective protein degradation in tumors remains a substantial challenge. Cancer cells depend on certain solute carrier (SLC) transporters to acquire extracellular nutrients to sustain their metabolism and growth. This current study exploits facilitative glucose transporters (GLUTs), a group of SLC transporters widely overexpressed in numerous types of cancer, to drive the endocytosis and lysosomal degradation of target proteins in tumor cells. GLUT-targeting chimeras (GTACs) were generated by conjugating multiple glucose ligands to an antibody specific for the target protein. We demonstrate that the constructed GTACs can induce the internalization and lysosomal degradation of the extracellular and membrane proteins streptavidin, tumor necrosis factor-alpha (TNF-α), and human epidermal growth factor receptor 2 (HER2). Compared with the parent antibody, the GTAC exhibited higher potency in inhibiting the growth of tumor cells in vitro and enhanced tumor-targeting capacity in a tumor-bearing mouse model. Thus, the GTAC platform represents a novel degradation strategy that harnesses an SLC transporter for tumor-selective depletion of secreted and membrane proteins of interest.

Peptidyl arginine deiminases (PADs) are important enzymes in many diseases, especially those involving inflammation and autoimmunity. Despite many years of effort, developing isoform-specific inhibitors has been a challenge. We describe herein the discovery of a potent, noncovalent PAD2 inhibitor, with selectivity over PAD3 and PAD4, from a DNA-encoded library. The biochemical and biophysical characterization of this inhibitor and two noninhibitory binders indicated a novel, Ca²⁺ competitive mechanism of inhibition. This was confirmed via X-ray crystallographic analysis. Finally, we demonstrate that this inhibitor selectively inhibits PAD2 in a cellular context.