JACS Au最新文献

The COVID-19 pandemic spurred the rapid development of nirmatrelvir, a main protease (M^pro) inhibitor now widely prescribed as part of Paxlovid (nirmatrelvir plus ritonavir). However, increasing use has raised concerns about drug resistance. Resistance selection studies have identified multiple M^pro mutations, with E166V emerging as a particularly resistant variant. Sequencing data from COVID-19 patients confirms E166V as a clinically relevant mutation, and importantly, this substitution also confers cross-resistance to several next-generation M^pro inhibitors under development. In response, this study reports the rational design of inhibitors active against nirmatrelvir-resistant E166V/A mutants. The lead candidate, Jun13698, shows potent inhibition of both wild-type M^pro and the E166V/A mutants. Structural studies and molecular dynamics simulations reveal that Jun13698 forms stable complexes with wild-type and mutant proteases, consistent with its potent enzymatic and antiviral activity. Together, these findings position Jun13698 as a promising next-generation M^pro inhibitor capable of overcoming clinically relevant nirmatrelvir resistance.

The most fundamental abstraction underlying all modern computers is the Turing Machine, that is, if any modern computer can simulate a Turing Machine, an equivalence which is called "Turing completeness", it is theoretically possible to achieve any task that can be algorithmically described by executing a series of discrete unit operations. In chemistry, the ability to program chemical processes and ensure unit operations are understood at a high level of abstraction and then reduced to practice is extremely challenging. Herein, we exploit the concept of Turing completeness applied to robotic chemical platforms that execute unit operations to synthesize complex molecules using a chemically aware programming language, XDL. We leverage the concept of computability by computers to synthesizability of chemical compounds by automated synthesis machines. The results of an interactive demonstration of Turing completeness using the color gamut and conditional logic are presented to serve as a proxy for conceptual, chemical space exploration. This formal description establishes a formal framework in future chemical programming languages to ensure complex logic operations are expressed and executed correctly, with the possibility of error correction, in the autonomous pursuit of increasingly complex molecules.

Csp ³-Cl bonds are essential as diversification handles in organic synthesis and are found in many natural products and bioactive molecules. In this work, we introduce a general protocol for the selective chlorination of aryl cyclopropanes, olefins, and activated C-H bonds using direct photoexcitation of Willgerodt-type reagents to generate chlorine radicals. Preliminary results for an iodine-(I/III) catalytic process starting from abundant chloride salts are also presented. Furthermore, a one-pot protocol has been developed for the telescoped functionalization of benzylic chlorides with C-, N-, O-, and S-nucleophiles. Especially, this approach provides a platform to access 1,1-diaryl motifs, which are important building blocks for the synthesis of pharmacophores.

[This corrects the article DOI: 10.1021/jacsau.5c00422.].

Boraindanes, composed of aromatic two-dimensional (2D) benzene and saturated three-dimensional (3D) boracycle moieties, are considered promising candidates for bioactive compounds/probes, agents for boron neutron capture therapy, and functional materials, as they combine the photophysical properties of the 2D aromatic and the high molecular recognition ability of the 3D boracycle. However, 2-boraindanes are difficult to access due to the difficulty of constructing two unstable C-(sp³)-B bonds. Herein, we present a straightforward synthesis of highly borylated, phenanthrene-fused 2-boraindane derivatives from biphenyl-linked terminal diacetylides through a B-B bond activation strategy. This methodology provides convenient access to a range of 2-boraindanes simply by changing the starting diyne. Spectroscopic measurements and computational analyses disclosed that the obtained highly borylated 2-boraindanes possess altered photophysical properties compared to the original 2D phenanthrene. The 2D/3D cyclic organoboron framework was utilized to construct a highly selective fluorescent probe for glucose.

Lysosome-targeting chimera technology has been utilized to degrade proteins of interest via the endosome-lysosome pathway mediated by endogenous ligands that engage cell-surface transmembrane proteins. Despite their promising potential, current approaches remain limited by the tissue-specific expression of surface receptors required for endocytosis. Prostate-specific membrane antigen (PSMA) is highly and specifically expressed in prostate cancer, driving significant progress in PSMA-targeted therapies, particularly radioligand therapy and antibody-drug conjugates, through PSMA-mediated internalization. Leveraging this phenomenon, we developed PSMA-targeting chimeras (PATACs), a novel and readily accessible class of heterobispecific small molecules designed for membrane protein degradation. PATACs facilitate the cointernalization of a target protein of interest, directing it into the lysosomal degradation pathway. As a proof of concept, A4, a representative PATAC, induced rapid and dose-dependent degradation of programmed cell death ligand 1 (PD-L1), with significant reduction observed within 4 h at concentrations up to 100 nM. Consequently, this degradation potently enhanced T-cell-mediated killing of LNCaP cells in a coculture system. Molecular dynamics simulations revealed that PATAC A4, featuring a short and rigid linker, exhibits enhanced conformational stability within the PSMA-A4-PD-L1 ternary complexes. These findings reveal PATACs as a promising new class of bifunctional small-molecule modalities for the precise manipulation of membrane proteins and targeted therapy in prostate cancer.

Rubbers are polymer networks that are used in many everyday applications ranging from tires to apparel. Unfortunately, the cross-links that give these materials their desirable properties also make them difficult to recycle. Covalent adaptable networks (CANs) are a promising class of cross-linked polymers that rearrange their cross-links in response to a stimulus like heat, making them more recyclable than conventional thermosets. Herein we present a method of incorporating dithioalkylidenes, a catalyst-free associative dynamic bond, into polybutadiene rubbers using olefin metathesis. The modified polymers are cross-linked with a multiarmed thiol, and the resulting networks are chemically and mechanically recycled. Evolution of the network microstructure during recycling results in up to a 7-fold increase in toughness over three cycles of recycling. We incorporate common fillers like carbon fiber and silica into CANs to provide reinforced composites and recover these fillers through chemical recycling. Finally, we modify devulcanized rubber crumb derived from rubber waste, enabling the preparation of mechanically recyclable composites with 90% upcycled content. This work presents a new method of upcycling waste rubber to access materials with multiple lifecycles.

Light-mediated intermolecular dehydro-Diels-Alder (DDA) reactions have emerged as a powerful strategy for constructing multisubstituted naphthalenesprivileged scaffolds found in natural products, pharmaceuticals, and functional materials. However, developing a general [4 + 2] cycloaddition system that accommodates electron-deficient dienes with both electron-rich and electron-deficient alkynes has remained challenging. Herein, we report a catalyst-free DDA reaction between sulfonyl-substituted aryl maleimides, serving as electron-deficient dienes, and alkynes under visible-light irradiation. By proceeding via a triplet intermediate manifold that bypasses conventional single-electron-transfer pathways and their redox matching constraints, this protocol enables efficient and regioselective access to diverse multisubstituted naphthalenes and exhibits broad compatibility with alkynes of varying electronic nature. Mechanistic studies reveal the essential dual role of the sulfonyl group in promoting the [4 + 2] cycloaddition with high chemoselectivity and facilitating the final aromatization step.

Cobalt- and copper-based oxides have emerged as cost-effective electrocatalysts for the electrochemical nitrate reduction reaction (NO₃RR) to ammonia. However, the cathodic potentials required for NO₃RR induce irreversible structural transformations that often compromise catalyst stability and selectivity, depending on the applied electrochemical protocol. To understand the resulting dynamic structure-performance relationships and improve nitrate-to-ammonia conversion, a tandem Co₃O₄/Cu _x O electrocatalyst was prepared by electrodeposition followed by thermal treatment, and two surface activation strategies were employed: by cycles of cyclic voltammetry (CV) or by holding at a constant potential by chronoamperometry (CA). The CA-reconstructed Co/Cu mixed oxide-derived electrocatalyst exhibited a higher faradaic efficiency (FE) toward ammonia across the entire potential window studied (0.00 to -0.40 V_RHE). The reconstruction effects induced by both electrochemical protocols were systematically investigated, revealing morphological, structural, and compositional changes that underpin the improved nitrate-to-ammonia conversion. Furthermore, in situ and online electrochemical techniques were employed to identify intermediates and active sites, providing new mechanistic insights into the electrochemical nitrate-to-ammonia conversion pathway. These findings contribute to understanding dynamic reconstruction phenomena and offer design guidelines for more stable and selective mixed oxide electrocatalysts for sustainable ammonia production.

Targeted protein degradation, particularly through molecular glue degraders (MGDs), offers a promising strategy for targeting "undruggable" proteins. However, existing fluorescence-based screening approaches, such as time-resolved fluorescence resonance energy transfer, may be constrained by conformational changes or inefficient labeling of targets, necessitating more efficient screening approaches. Here, we present a MGDs screening approach based on surface plasmon resonance (SPR) coupled with degradomics and interactomics (SPR-DI). This approach leverages the high-throughput and label-free SPR for screening E3 ligands, followed by an unbiased "dual filter" of degradomics and interactomics to identify candidate proteins of interests (POIs). The feasibility of SPR-DI was validated using previously established MGD VH032, which can drive VHL to induce CDO1 degradation. Employing VHL and Keap1 as drivers E3, we then screened a natural product library and successfully identified triptolide and pycropodophyllin as potential MGDs. Subsequent investigations demonstrated that triptolide facilitates VHL-mediated degradation of IMP3, whereas picropodophyllin promotes Keap1-mediated degradation of DDX52 and LDHB. These degradation events were confirmed to depend on the respective E3 and ubiquitin-proteasome system, underscoring the capacity of these compounds to induce ternary complex formation. In conclusion, the establishment of SPR-DI provides a promising tool for the discovery of MGDs and their corresponding POIs, offering instructive insights to advance future MGD screening methodologies.