Targeting RNA-binding proteins (RBPs) that control mRNA turnover presents a promising avenue for modulating gene expression and accessing otherwise "undruggable" intracellular targets. MEX3C is a tumor- and tissue-specific RBP that facilitates transcript destabilization by recruiting the CCR4-NOT deadenylation complex; however, selective tools to perturb MEX3C are lacking. Here, we report the development of a high-affinity and specific DNA aptamer through iterative Blocker-SELEX selection and sequence optimization. The resulting aptamer, MRiApt, binds the KH1 domain of MEX3C with nanomolar affinity and competitively inhibits RNA binding while sparing the homologous KH2 domain. A chemically stabilized derivative, MRiApt-PT-stem, exhibits enhanced stability and efficient intracellular uptake and effectively antagonizes the MEX3C-dependent repression of HLA-A2 transcripts, restoring HLA-A2 expression and thereby improving tumor cell recognition by T cells. Analysis of TCGA data revealed that high-MEX3C expression was significantly associated with poor prognosis in liver hepatocellular carcinoma (LIHC), underscoring the clinical relevance of perturbing MEX3C. Together, these findings establish MRiApt-PT-stem as a chemical probe to dissect and modulate MEX3C-mediated post-transcriptional regulation, providing a foundation for future approaches in transcriptome modulation and therapeutic targeting of RBPs.

Three new lindenane-type sesquiterpenoids (1, 2, and 4), together with fifteen known analogues, were isolated from the roots of Lindera aggregata (Sims) Kosterm. (Lauraceae), a well-known traditional Chinese medicinal plant. Infections caused by Candida albicans have become a serious clinical concern due to the increasing emergence of drug resistance and the shortage of highly selective antifungal agents. Lindenane-type sesquiterpenoids are characteristic constituents of L. aggregata with diverse structures and a broad spectrum of biological activities; however, their antifungal potential has rarely been explored. Their structures were elucidated by comprehensive spectroscopic analyses and ECD calculations. In the antimicrobial assay, compounds 1-6, 8, 12, and 14 exhibited selective and potent inhibitory activity against C. albicans, with MIC values ranging from 4-8 µg/mL, whereas they exhibited weak or no antibacterial effects. This study expands the structural diversity of lindenane-type sesquiterpenoids and offers new antifungal lead scaffolds from a natural source.

Systematic genome mining has revealed that microbes encode numerous uncharacterized secondary metabolite biosynthetic gene clusters (BGCs). The efficient and selective activation of these silent or cryptic BGCs is crucial for the high-throughput discovery of novel natural products. Recent influential studies have demonstrated that using small chemical elicitors is a practical and cost-effective method to unlock the secondary metabolic potential of microbes. However, the current approach mainly relies on high-throughput, non-targeted screening methods to discover chemical elicitors capable of activating these silent BGCs. Therefore, this study comprehensively reviews reported cases of small molecules that activate silent BGCs, covering the chemical structures of elicitors, resulting natural products, and target BGCs, thereby constructing an integrated knowledge graph. We also summarize the underlying activation mechanisms. Leveraging relationships captured in this graph, we outline directions for targeted activation of silent pathways using small molecules, thereby facilitating more efficient natural product discovery.

Marine natural products (MNPs) have emerged as a vital source of novel antibiotic lead compounds due to their unique chemical architectures and remarkable antibacterial activities. This review systematically summarizes recent advances (2020–2024) in antibacterial marine-derived analogues, with a focus on their structural elucidation, pharmacological properties, and structure–activity relationships (SAR). The discussed compounds are primarily isolated from sponges, corals, tunicates, and marine microorganisms, and structurally categorized into alkaloids, polyketides, peptides, polysaccharides, and macrolides. These molecules frequently exhibit complex polycyclic frameworks, halogen substitutions (e.g., bromine and chlorine), and glycosylation patterns, which critically govern their antibacterial potency and selectivity. Studies reveal that most compounds display significant inhibitory effects against clinically resistant strains such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, with minimum inhibitory concentrations of several lead compounds reaching nanomolar levels. SAR analyses elucidate the pivotal roles of structural elements, including halogenation patterns, alkyl chain length, glycosylation degree, and stereochemistry, in modulating antibacterial efficacy. This review aims to provide a theoretical foundation and resource reference for the development of innovative antibacterial agents, while also outlining future challenges and research directions in the field of marine-derived antibacterial drug discovery.

Gut microbial β-glucuronidase has attracted attention as a potential therapeutic target for mitigating irinotecan (CPT-11)-induced late-onset diarrhea and intestinal injury. Here, we designed and synthesized 60 thioester derivatives bearing a 1,3,4-thiadiazole moiety and evaluated their biological activities. In vitro, 3-5B (IC50 = 0.39 μM) exhibited potent inhibitory activity against Escherichia coliβ-glucuronidase (EcGUS). Kinetic studies showed that 3-5B acts as an uncompetitive EcGUS inhibitor (Ki = 0.60 μM). Furthermore, molecular docking analysis suggested that 3-5B binds EcGUS with high affinity through interactions with residues Asp163, Glu413, and Trp549. Notably, 3-5B showed no inhibitory effect on bovine liver β-glucuronidase, did not inhibit E. coli growth, and exhibited low cytotoxicity toward human Caco-2 cells. In vivo, oral administration of 3-5B (1 mg/kg/d) attenuated CPT-11-induced gastrointestinal toxicity in BALB/cJ mice, including weight loss, diarrhea, and colonic injury. Collectively, these findings identify 3-5B as a promising lead scaffold for the development of EcGUS inhibitors.

Aspergillus fungi are rich in secondary metabolites, yet their biosynthetic potential remains underexplored. Nonribosomal peptides (NRPs), an important class of natural products with diverse biological activities, are synthesized by nonribosomal peptide synthetases (NRPSs). In this study, we performed a large-scale bioinformatic analysis of NRPS adenylation (A) domains from 1,162 Aspergillus genomes to predict their substrate specificities. Using AdenylPred, we analyzed 40,684 A-domain sequences and found that large phenyl-derivative amino acids and small hydrophobic amino acids are the predominant substrates, accounting for 66

Activation of intestinal bitter taste receptors can stimulate the release of glucagon-like peptide-1 (GLP-1), thereby enhancing insulin secretion and exerting a hypoglycemic effect. In this study, a combination of bioactivity-guided screening and chemical analysis was applied to search for potential components from Momordica charantia L. that exert hypoglycemic effects via bitter taste receptors. Combined with molecular networking and DeepSAT analysis, the active fraction was found to be rich in cucurbitane-type triterpenoids, from which five pure compounds were isolated and identified. In conjunction with LC-Q-TOF-MS/MS analysis, an additional 24 cucurbitane-type triterpenoids were also identified from the active fraction. Bioactivity evaluation revealed that five compounds exhibited stimulatory effects on GLP-1 secretion in Caco-2 cells; Compounds 2 and 4 increased GLP-1 secretion to 1.40-fold and 1.35-fold of the basal level at 5 µM, respectively. These results indicate that cucurbitane-type triterpenoids may responsible for the potential hypoglycemic effect of M. charantia L. via bitter taste receptors. PRACTICAL APPLICATIONS: Cucurbitane-type triterpenoids derived from M. charantia L. are capable of stimulating the secretion of GLP-1 in intestinal cells, indicating their potential hypoglycemic activity. These compounds are promising as natural bioactive substances for the development of functional foods aimed at blood glucose homeostasis regulation. Furthermore, this provides a valuable research direction for the screening of natural hypoglycemic agents based on bitter taste receptors.

Bladder cancer (BCa) is one of the most prevalent malignancies worldwide, and the clinical treatment effect is limited due to the resistance and the associated low survival rates in patients. A10, as a novel camptothecin (CPT) derivative, possesses potent anti-tumor activity by targeting Topo Ⅰ/DDX5 (p68). However, the poor aqueous solubility and low bioavailability of A10 restrict its further application. We developed a Soluplus® - based solid dispersion (A10-SD) to enhance solubility by 389-fold and oral bioavailability by 14.38-fold. This research provided evidence of the immune activation induced by A10 against BCa T24 cells, and A10 could activate the cGAS-STING pathway, promote DAMPs release, and induce Immunogenic Cell Death (ICD) for anti-tumor activity against BCa cells in vitro. A10-SD meanwhile demonstrated remarkable tumor-suppressive efficacy in vivo with TGI of 99.84%, and its immune activation was preliminarily confirmed in vivo. A10-SD also showed good safety. This strategy provides an effective approach for the development of orally administered poorly soluble compounds, helping to unlock their therapeutic potential and promote their application.

Medium-sized rings are valuable synthetic scaffolds yet challenging to construct. Herein, we report a Lewis-acid-catalyzed (8 + 3) cycloaddition of bicyclo[1.1.0]butanes with alkenyl cyclic dithioacetals that provides efficient access to previously inaccessible 11-membered bicyclo[8.1.1] skeletons. Driven by strain release and catalyzed by Lu(OTf)3, this ring expansion proceeds under mild conditions, exhibits a broad substrate scope, and delivers products in excellent yields (46 examples, with yields up to 94%). Mechanistic studies and DFT calculations support a pathway involving sequential nucleophilic attack, ring opening, and regioselective intramolecular 1,4-addition.

The global rise of methicillin-resistant Staphylococcus aureus (MRSA) has highlighted the urgent need for alternative therapeutic strategies beyond conventional bactericidal antibiotics. Targeting bacterial virulence rather than viability represents a promising approach to mitigate selective pressure and delay resistance development. Sortase A (SrtA), a membrane-associated transpeptidase responsible for anchoring virulence-associated surface proteins, is an attractive anti-virulence target due to its non-essential role in bacterial survival. Here, we report a machine learning-guided strategy for the discovery of novel covalent SrtA inhibitors based on a 1,2-benzoselenazol-3-one (BSEA) scaffold featuring a tunable electrophilic Se-N bond. A scaffold-aware classification model with a Tanimoto similarity constraint trained on 529 SrtA inhibitors enabled prospective virtual screening of over 35,000 BSEA and BTA derivatives, leading to a high hit rate of 89% upon experimental validation. Representative compounds exhibited submicromolar SrtA inhibition (IC50 = 0.84-1.04 μM) while showing minimal effects on bacterial growth (MIC = 8-32 μM), indicating effective functional decoupling of virulence and viability. Mechanistic studies demonstrated time-dependent irreversible inhibition kinetics, supported by jump dilution assays and Nano-LC-MS/MS identification of covalent modification at the catalytic residue Cys184. These inhibitors effectively disrupted MRSA biofilm formation at sub-inhibitory concentrations and significantly improved host survival in a Galleria mellonella infection model. Collectively, this study establishes a data-driven framework integrating machine learning and covalent chemistry for anti-virulence drug discovery and provides promising lead compounds targeting SrtA to combat MRSA infections.

An enantioselective Michael/O-alkylation cascade between hydroxyquinolines and chloronitroalkenes was developed, constructing chiral dihydrofuroquinoline scaffolds in high enantioselectivity under mild conditions. The direct modification of hydroxylcamptothecin and the discovery of anti-tumour (MCF-7 cell lines) leads highlight the potential of this process.

Bladder cancer is a malignant tumor with a high incidence and mortality worldwide. Clinically, DNA-damaging agents such as cisplatin, irinotecan, and gemcitabine are commonly used, but their efficacy is often limited by acquired resistance. A key resistance mechanism involves the upregulation of PARP1 in response to drug-induced DNA single-strand breaks (SSBs), which diminishes the therapeutic effect. To overcome this obstacle, we designed and synthesized a series of united TOP1/PARP1 inhibitors that simultaneously induce SSBs via TOP1 inhibition and block their repair via PARP1 inhibition, converting repairable SSBs to lethal double-strand breaks (DSBs). Among these, compound D5 exhibited excellent dual-target inhibitory activity and effectively overcame cisplatin resistance, demonstrating potent antitumor efficacy in vitro and in vivo (TGI = 65.7%). Collectively, D5 represents a promising TOP1/PARP1 inhibitor for overcoming resistance to conventional DNA-damaging chemotherapies.

A 13-step asymmetric total synthesis of (-)-cribrostatin 4 is disclosed. The synthetic route begins with the development of an asymmetric double hydrogenation of 2,5-diketopiperazine-derived enamides enabled by a novel spiropyrrolidine-derived diphosphine (SPDP) ligand. Employment of mono- and oxidative Pictet-Spengler cyclizations allows for expedient construction of the tetrahydroisoquinoline and benzo[3.3.1]-bridged rings along with an enamide alkene. At a late stage, an unprecedented stereochemical editing approach for direct β-epimerization of a primary alcohol was developed by virtue of borrowing hydrogen catalysis. Collectively, these methodological advances contribute to a concise synthesis of this structurally unique bis-tetrahydroisoquinoline (bis-THIQ) alkaloid.

Antimicrobial resistance exacerbates the difficulty of clinical bacterial infection treatment, as single-target antibiotics rapidly lose efficacy shortly post-clinical use. Such resistance highlights an urgent need for multitargeted therapeutics. Metalloantibiotics, combining metal ions with antimicrobials to disrupt diverse bacterial pathways, represent a promising strategy to circumvent resistance. Here, we engineer a sideromycin-bismuth molecular nanoassembly for treating ciprofloxacin-resistant Pseudomonas aeruginosa. Using phylogenomics-driven methods, we identify four hydroxamate siderophores from Streptomyces fradiae and rationally design sideromycin 7 by a structure-based strategy. Sideromycin 7 forms a 7-Bi3+ coordination complex with bismuth citrate, exerting a three-pronged antibacterial mode of action: direct DNA binding to induce damage and arrest replication, suppression of KdpC synthesis to block KdpFABC-mediated potassium transport, and inhibition of ATP production. In murine models, this combination therapy exhibits potent efficacy against ciprofloxacin-resistant P. aeruginosa with a considerable safety index. Our findings highlight the potential of phylogenomics-guided metalloantibiotic engineering for overcoming drug resistance.

The escalating global crisis of bacterial multidrug resistance (MDR), particularly the recalcitrant infections caused by Pseudomonas aeruginosa, underscores an urgent need for novel therapeutic strategies. In contrast to conventional bactericidal antibiotics, antivirulence approaches targeting the quorum sensing (QS) system offer a promising paradigm by attenuating pathogenicity without exerting lethal selective pressure, thereby potentially mitigating resistance development. This review provides a comprehensive and systematic analysis of the research progress on heterocyclic derivatives as QS inhibitors reported between 2020 and 2025. It is specifically focused on two principal structural classes: nitrogen-containing heterocycles (e.g., quinolines, (inhibition rate: 40.3%-87.4%), quinazolines (IC50 = 0.3-6.9 μM), pyridines (IC50 = 0.3-6.6 μM), indoles (IC50 = 0.2-0.3 μM), thiazoles (IC50 = 0.4-131.5 μM)) and oxygen-containing heterocycles (e.g., furans (inhibition rate: 53.0%-86.8%), flavonoids (inhibition rate: 32.0%-90.9%), coumarins (inhibition rate: 50.0%-73.0%)). For these compounds, biological activities, structure-activity relationships, and targets are critically discussed. This work aims to consolidate recent advances and offer valuable insights for the rational design and development of next-generation anti-infective agents targeting bacterial communication pathways.

A Brønsted acid-promoted exo-cyclization of bicyclo[1.1.0]butyl ketones with hydrazines has been established. This approach enables efficient ring expansion, leading to a diverse range of 2,3-diazabicyclo[3.1.1]heptenes. Mechanistic studies reveal that the carbonyl group is pivotal, fulfilling a dual role as both the reactive center and a latent activating group. Moreover, the unique dual nucleophilic character of hydrazines, featuring two nitrogen-based nucleophilic sites, is crucial to the success of this transformation.

Excessive pesticide exposure is increasingly associated with oxidative stress mediated reproductive toxicity. Pyriproxyfen (PPF), a widely used juvenile hormone analog insecticide, has been implicated in oxidative stress mediated reproductive toxicity. This study investigated the mechanisms underlying PPF-induced testicular damage and evaluated the protective potential of Ephedra pachyclada extract (EPE), focusing on modulation of the Nrf2/ARE and NF-κB pathways. Adult male rats were exposed to PPF (20 mg/kg body weight) with or without EPE administration (140 mg/kg body weight). Oxidative stress biomarkers, inflammatory mediators, steroidogenic gene expression, serum testosterone, sperm parameters, and histopathological alterations were assessed. LC-MS analysis characterized the phytochemical composition of EPE. PPF exposure significantly increased lipid peroxidation and reduced antioxidant enzyme activities, accompanied by downregulation of Nrf2 and its downstream targets. In parallel, NF-κB expression and pro-inflammatory cytokines were elevated. These molecular disturbances were associated with suppression of StAR, SR-B1, CYP11A1, 3b-HSD, and 17b-HSD expression, decreased testosterone levels, reduced sperm count and motility, increased sperm abnormalities, and structural degeneration of seminiferous tubules. EPE administration markedly attenuated oxidative stress, restored Nrf2 signaling, suppressed inflammatory responses, normalized steroidogenic gene expression and testosterone levels, and improved sperm quality and testicular histology. LC-MS profiling revealed a predominance of flavonol glycosides, flavone C-glycosides, flavan-3-ols, and biflavonoids. These findings suggest that EPE mitigates PPF-induced reproductive toxicity through restoration of redox and inflammatory homeostasis.

Pinynditerpene A (1), an unprecedented abietane diterpenoid featuring a unique 6/5/6/5-fused indeno[7,1-bc]furan skeleton with 5 consecutive chiral centers, was isolated from Pinus yunnanensis resins. Its structure was elucidated by spectroscopic, computational, and crystallographic methods. 1 was found to be able to alleviate inflammation associated depression-like behaviors in mice, exerting its significance in mood disorders.

Overcoming multidrug resistance (MDR) remains a formidable obstacle in cancer chemotherapy, largely attributable to drug efflux mediated by the P-glycoprotein (P-gp) pump. To address this challenge, we designed and synthesized 27 novel phenylindole derivatives and systematically assessed their MDR-reversal activity in MCF-7/ADR cells. Among these compounds, Ina4 demonstrated potent reversal activity (RF = 229.4), exceeding that of the reference P-gp inhibitors verapamil (RF = 51.0) and cyclosporine A (RF = 103.3), while exhibiting low intrinsic cytotoxicity. Mechanistic investigations, including western blot and Rhodamine 123 (Rh123) accumulation assays, revealed that Ina4 effectively inhibits the efflux function of P-gp without altering its protein expression levels. Furthermore, molecular docking analysis indicated that Ina4 may bind to the active pocket of P-gp, primarily via π-π stacking interactions. Notably, in a 3D tumor spheroid model, co-administration of Ina4 with doxorubicin (DOX) resulted in significant suppression of spheroid growth. Collectively, these findings indicate that Ina4 is a promising P-gp inhibitor.