Targeted protein degradation (TPD) represents a promising approach for eliminating disease-causing proteins beyond traditional inhibition. However, the reliance on a limited number of E3 ligases remains a major bottleneck. FEM1B, an E3 ligase substrate receptor with multiple substrate-recognition modes, represents an attractive but underexplored TPD platform. In this study, through a structure-guided approach exploiting the spatial proximity between a druggable C-degron-binding pocket and a second binding site containing a reactive cysteine, we developed FL47, a dual-site ligand that combines extensive noncovalent interactions with targeted covalent engagement. FL47 exhibits submicromolar affinity, robust cellular target engagement, and markedly reduced cytotoxicity relative to previously reported covalent recruiters. We further applied FL47 in the development of FEM1B-based PROTACs and incorporated a chemical endocytic prodrug strategy that markedly enhanced degradation activity. This work introduces a novel dual-site binding strategy for E3 ligase ligand discovery and broadens the potential toolbox for TPD applications.

α-Glucosidase inhibitors mitigate postprandial hyperglycemia by delaying carbohydrate hydrolysis. Guided by the principle of bioisosterism, we transformed an acid-labile benzylidene acetal sulfonium scaffold into acid-stable C-glycosyl pyranose-based sulfonium and selenonium salts. The lead, 38f, inhibited rat intestinal maltase and sucrase with IC50 values of 0.10 and 0.08 μM, respectively, outperforming acarbose and voglibose, and showed excellent stability in simulated gastric fluid and intestinal fluid. In vivo, 38f delivered robust, dose-efficient glucose lowering: at 1-3 mg/kg, it markedly suppressed postprandial excursions in normal ICR mice and reduced fasting glucose in STZ-diabetic mice (3 mg/kg 32.8% vs acarbose 50 mg/kg 24.3%). Across OGTT/ITT and maltose/sucrose tolerance tests, 38f improved glycemic end points, liver glycogen, and HbA1c. Kinetic analyses support competitive inhibition of α-glucosidase. A 14-day subacute study (≤500 mg/kg) indicated an acceptable safety profile without hepatic or renal toxicity. These acid-resistant C-glycosyl pyranose cationic glycomimetics merit further development as antidiabetic agents.

ABSTRACT Redox‐buffering systems in tumors heighten chemoresistance, yet most ROS‐responsive linkers used in prodrug design consume oxidants, exhibit limited sensitivity to endogenous ROS, and often require external triggers or complex formulations, constraining clinical translation. Here we report a phenylselanyl cyclohexenone self‐immolative linker that couples ROS‐triggered cleavage with organoselenium‐mediated redox amplification within a single small‐molecule architecture. Oxidation of the selanyl group generates a selenoxide that undergoes aromatization‐assisted β‐elimination followed by 1,6‐self‐elimination, releasing the payload together with a redox‐active selenium species. The released selenium species is proposed to engage in a GSH‐dependent redox cycle that increases intracellular oxidative burden, thereby reinforcing ROS‐triggered activation and weakening antioxidant buffering. This modular motif enables the construction of carrier‐free prodrugs spanning chemotherapeutics and small‐molecule inhibitors. These prodrugs remain stable in neutral media yet are efficiently activated by endogenous ROS, achieving improved biodistribution, reduced systemic toxicity, and enhanced antitumor activity across breast cancer, pancreatic ductal adenocarcinoma, and patient‐derived leukemia models. By coupling selective activation with catalytic redox amplification, this ROS‐amplifying self‐immolative linker provides a modular strategy for overcoming redox‐associated drug resistance and for advancing the translational potential of small‐molecule prodrugs.

Developing effective α-glucosidase inhibitors is critical for managing hyperglycemia in individuals with high-carbohydrate diets; however, current drugs exhibit limitations in both efficacy and tolerability. In the present study, 25 derivatives of neoponkoranol, an active sulfonium type α-glucosidase inhibitor identified from Genus Salacia were synthesized. These compounds containing a methyl-glycosyl furanose scaffold modified with various hydrophobic groups at the 5'-O-position, were characterized using HRMS and NMR spectroscopy. Biological evaluations demonstrated a selectively enhanced maltase inhibition profile while maintaining broad-spectrum activity. Most sulfonium salts exhibited potent inhibitory activity against maltase and sucrase with IC50 values ranging from 0.14 to 2.21 μM; these potencies are comparable to or superior to those of the positive controls acarbose and voglibose. In addition, the designed derivatives also exhibited strong isomaltase inhibitory activities whereas acarbose was almost inactive against this enzyme. Compound LY-23 emerged as the most potent inhibitor with maltase IC50 = 0.18 ± 0.03 μM, sucrase IC50 = 0.14 ± 0.01 μM, and isomaltase IC50 = 0.51 ± 0.06 μM. Mechanism studies characterized LY-23 as a competitive inhibitor. Molecular docking along with 3D fluorescence and CD spectral analyses indicated that LY-23 binds to α-glucosidase, inducing secondary structural and conformational changes in the enzyme. Furthermore, LY-23 showed no significant cytotoxicity in HEK293T and L02 cells. Remarkably, in vivo studies revealed that the oral administration of LY-23 (1.0 or 10.0 mg/kg) effectively reduced postprandial blood glucose levels in normal ICR mice following maltose or sucrose loading, with an efficacy comparable to that of voglibose (1.0 mg/kg) and acarbose (20.0 mg/kg), respectively. These findings highlight LY-23 as a promising candidate for the development of novel α-glucosidase inhibitors with antihyperglycemic properties.

IntroductionChromoblastomycosis (CBM) is a chronic cutaneous infection caused by dematiaceous fungi, characterized by therapeutic challenges such as difficulty in pathogen clearance and high recurrence rates. Fonsecaea pedrosoi (F. pedrosoi), the most common etiological agent of CBM, relies on its virulence factor DHN-melanin to evade host immune responses—especially by suppressing neutrophil function—further contributing to disease persistence and treatment resistance. Thus, we intended to explore therapeutic approaches that target both fungal virulence mechanisms and host immune regulation to overcome the clinical hurdles of CBM.ObjectivesThis study aimed to investigate the effects of tricyclazole (TCZ) on F. pedrosoi and neutrophil antifungal responses, with a particular focus on its potential actions in inhibiting DHN-melanin synthesis and enhancing host oxidative immune mechanisms.MethodsWe conducted in vitro assays to assess the effects of TCZ on F. pedrosoi melanin and fungal antioxidant enzymes, as well as reactive oxygen species (ROS) production and neutrophil extracellular traps (NETs) formation in human neutrophils. The in vivo mouse model was used to evaluate inflammatory responses, neutrophil-related markers, and fungal clearance.ResultsIn vitro tests showed TCZ dose-dependently inhibited fungal DHN-melanin synthesis and disrupted the antioxidant enzyme system (including superoxide dismutase and catalase); this effect not only weakens the fungus’s ability to resist host oxidative stress but also reduces its capacity to evade immune recognition, creating conditions for subsequent immune clearance. In vitro co-culture models revealed that TCZ significantly enhanced neutrophil ROS production and NET formation; this strengthens the oxidative killing function of neutrophils, directly counteracting the immunosuppressive effect of DHN-melanin on neutrophils and improving the host’s ability to eliminate pathogens. In a mouse infection model, TCZ treatment significantly alleviated pedal inflammation, reduced neutrophil activation markers, and completely eliminated fungal colonization; these results validate TCZ’s in vivo therapeutic efficacy, demonstrating its potential to mitigate inflammatory tissue damage while achieving effective fungal eradication.ConclusionsThis study reveals a novel mechanism by which TCZ counteracts F. pedrosoi-mediated suppression of neutrophil antifungal effector functions, particularly oxidative burst and NET formation, thereby facilitating fungal clearance in CBM. These findings provide a novel strategy for CBM treatment by integrating immunomodulation with antifungal therapy.

ABSTRACT Reactive sulfur species derived from hydrogen sulfide are central regulators of redox signaling; however, sulfenic acid (HSOH) has remained largely inaccessible owing to the absence of chemically defined donor systems. Here we report a mechanistically delineated strategy for controlled HSOH generation based on an intramolecular cyclization–release platform incorporating an aminosulfine (thioamide S‐oxide) motif. Aminosulfine derivatives containing an ester group can undergo a unique acyl transfer process via the nucleophilicity of the α‐amide ion, followed by intramolecular cyclization to release HSOH, providing a chemically tractable route for transient HSOH release. Systematic structure–activity relationship and kinetic studies further indicate that achieving efficient HSOH release requires precise kinetic matching between the acyl transfer rate and the intramolecular cyclization rate. Using complementary chemical trapping approaches and a persulfide‐selective fluorescent probe, we demonstrate that transiently generated HSOH exhibits exceptionally high reactivity, rapidly undergoing disproportionation and efficiently promoting thiol persulfidation even at low concentrations. Importantly, HSOH signaling confers protection against oxidative injury in a cellular oxygen–glucose deprivation model. This work establishes a chemically defined framework for probing HSOH‐initiated sulfur signaling and provides fundamental insights into the reactivity and biological implications of this elusive reactive sulfur species.

Drug-target interaction (DTI) prediction is a crucial task in computational drug discovery and repurposing, as it accelerates candidate identification while reducing development costs. Despite the advancements in deep learning, existing methods still face challenges in effectively modeling multi-modal data, fusing heterogeneous features, and capturing complex nonlinear relationships. We propose KAN-MoDTI to tackle these challenges by integrating Kolmogorov-Arnold Networks (KAN) with multimodal feature fusion and adaptive gating mechanisms, effectively combining heterogeneous drug and target representations to better capture the complex interactions between them. In the feature encoding stage, we use a dual-branch approach: For drugs, we combine SMILES sequence embeddings with structural representations from a KAN-based graph encoder. For targets, we integrate N-gram sequence embeddings with biochemical descriptor features. In the feature fusion stage, we introduce the FeatureFusionKAN module, which uses a gating mechanism to assign adaptive weights and KAN to perform the integration of heterogeneous modal features. KAN is also utilized in the final prediction layer to enhance the model's ability to accurately predict complex drug-target interactions. Comprehensive experiments on datasets such as DrugBank, BindingDB, and Human show that KAN-MoDTI consistently outperforms or matches recent state-of-the-art baselines across metrics like AUROC and AUPRC.The source code implementation can be found at: https://github.com/jiahaoxin/KAN-MoDTI.

Background: The peptidyl-prolyl cis-trans isomerase PIN1 regulates multiple oncogenic and tumor-suppressive pathways and is frequently overexpressed in human cancers. Although pharmacological inhibition of PIN1 has shown antitumor potential, existing PIN1-targeting degraders lack systematic structure-activity relationship (SAR) analyses and display inconsistent cellular efficacy, leaving the therapeutic relevance of PIN1 degradation unclear. Methods: Two series of PIN1-targeting PROTACs were designed using the covalent inhibitor sulfopin as the PIN1 binder and ligands for either cereblon (CRBN) or von Hippel-Lindau (VHL). Systematic SAR studies focused on linker structure and jointing atom composition. PIN1 degradation was assessed by Western blotting in multiple cancer cell lines, and further investigated through a series of computational and mechanistic experiments. Antitumor efficacy and safety were evaluated in an MCF-7 xenograft mouse model with preliminary pharmacokinetic analysis. Results: SAR analysis revealed that short, linear linkers and reduced hydrogen bond donor content markedly enhanced PIN1 degradation, whereas VHL-recruiting PROTACs showed inferior cellular activity. These studies identified PC2, a CRBN-recruiting PROTAC, as a lead compound. PC2 selectively induced ubiquitin-proteasome-dependent PIN1 degradation with minimal global proteomic or transcriptomic perturbation. Despite modest antiproliferative effects in vitro, PC2 significantly suppressed tumor growth in vivo without observable toxicity and achieved effective intratumoral PIN1 degradation. Conclusions: This study defines SAR-guided design principles for PIN1-targeting PROTACs and demonstrates that selective PIN1 degradation can produce robust antitumor activity in vivo. PC2 represents the first PIN1 degrader validated in animal models and supports targeted PIN1 degradation as a viable anticancer strategy.

Phenylethanoid glycosides (PGs), featuring a phenylethanoid glucoside core, exhibit diverse biological activities, notably neuroprotective effects. However, PGs bearing the susceptible 2'-O-acetyl group remain scarcely explored owing to their limited natural occurrence and the difficulty of preserving esters during synthesis. Herein, we describe the synthesis of such PGs, keeping the 2'-O-acetyl group intact via a remote DPPA-directed glycosylation strategy. The 2-(diphenylphosphinoyl)acetyl (DPPA) group ensures high stereocontrol through hydrogen-bonding in glycosylation, and can be selectively removed under mild Mg(OMe)2-promoted conditions. This approach enables streamlined access to both acetylated and non-acetylated PGs, including cistanosides E, G, and H, as well as the proposed structure of lophanthoside A. The developed method provides a general platform for constructing PGs bearing acyl groups and supports further investigation of their bioactive mechanisms.

Nucleosides are the most widespread and fundamental N-glycosides in biological processes. Despite their prevalence in nature and significance of their analogs in medicinal chemistry, conventional synthetic approaches rely on complicated upstream preparation including well-designed glycosyl donor and pre-silylated nitrogen-containing acceptor. Here we report a direct coupling strategy delivering purine glycoside by the N-glycosylation between natural sugar and purine in aqueous solution. The transformations are realized by one simple and concise step using a new imidazolinium chloride salt, with high chemo-, regio-, and stereo-selectivity. These findings greatly simplify access to various nucleoside analogs. Mechanistic studies suggest that sugar and purine are respectively activated by the imidazolinium cation and chlorine anion of the reagent.

The stereoselective construction of 1,1'-glycosidic linkages represents a significant challenge, as it typically results in a mixture of four possible anomers. Herein, we report a novel and efficient method to achieve this transformation leveraging a remote directing 2-(diphenylphosphinoyl)acetyl (DPPA) group on donors for catalytic glycosylation. This approach provides exceptional dual anomeric stereocontrol for both glycosyl donors and acceptors, which we attribute to the DPPA's role as a powerful hydrogen-bonding (H-bonding) acceptor.

Carbohydrates play pivotal roles in numerous biological processes. The precise synthesis of structurally defined and pure carbohydrates is of paramount importance in pathological research and drug development. However, achieving stereo- and regioselective glycosylation during carbohydrate synthesis is often a tedious process that exhibits low atom economy. Herein, we present a surprisingly simple yet synergistic combination of BF3Et2O in THF as a green solution to shorten the synthetic procedures, utilizing readily accessible imidate donor mixtures, regardless of their anomeric configuration. Glycosylation selectively occurs on the more nucleophilic hydroxyl group, giving 1,2-trans glycosides across a broad substrate scope in a highly stereo- and regioselective manner. This strategy is easy to apply and scale up, as demonstrated by an atom-economical synthetic route to achieve an oligosaccharide framework related to the Enterococcus faecalis antigen. Variable-temperature (VT) NMR studies revealed the formation of BF3ROH complexes, suggesting their roles as the true promoters and acceptors during glycosylation. Density functional theory (DFT) calculations suggested that 1,2-trans selectivity arises from the energy discrepancy between putative transition states involving [BF3OR]- and the oxocarbenium-solvent complex.

The aim of this study was to systematically appraise and synthesize real-world data of motor function and safety in Asian patients with spinal muscular atrophy (SMA) treated with nusinersen or risdiplam. This study systematically searched PubMed, Cochrane, Embase, CNKI, and Wanfang databases for real-world studies (RWS) published from January 2017 to January 2024. Based on the prespecified study selection and eligibility criteria, RWS evaluating motor function and/or safety outcomes in patients with types 2–4 SMA treated with nusinersen or risdiplam were included, while studies without Asian populations were excluded. The Newcastle–Ottawa Scale (NOS) was used to assess the risk of bias, and a meta-analysis was conducted for each motor function endpoint based on the extracted data. A total of 26 RWS were included in this review, of which 17 reporting main motor function outcomes were included in the meta-analyses. Intervention in all 17 studies was nusinersen; none included risdiplam. Statistically significant improvement was observed in Revised Upper Limb Module (RULM) [Mean difference (MD) = 2.27 (0.84, 3.71)], Hammersmith Functional Motor Scale Expanded (HFMSE) [MD = 2.62 (1.79, 3.45)] and six-minute walk test (6MWT) [MD = 18.29 (9.12, 27.45)] when treated with nusinersen ≤ 6 months and > 6 months (HFMSE [MD = 4.34 (3.54, 5.14)]; 6MWT [MD = 45.59 (12.92, 78.27)]). Clinically meaningful responses of motor milestones were also observed when treating nusinersen over 6 months: 54.4

Chrysanthemic acid is an unconventional monoterpene moiety of the natural pesticide pyrethrins with notable anti‐insect activity, making its industrial biosynthesis a promising avenue for sustainable agriculture. Here, an E. coli cell factory is designed and build for highly efficient chrysanthemic acid production guided by Genome‐scale metabolic models (GEM). The biosynthetic pathway is reconstructed and simulated the metabolic changes caused by exogenous modules are simulated. A key metabolic branch point catalyzed by ispA is identified by this model, and inhibiting its expression using synthetic small RNA redirected the metabolic flux, resulting in the titers of precursor chrysanthemol and chrysanthemic acid increasing by 162% and 59%, respectively. The effect of the expression level of downstream dehydrogenases on chrysanthemic acid titer is also predicated using GEM, and the further optimization of copy number for dehydrogenase genes led to a notably 570% increase in chrysanthemic acid titer experimentally. By integrating the debranching strategy with copy number optimization, a record chrysanthemic acid titer 141.78 mg L −1 is achieved in a bioreactor. The work seamlessly integrated in silico modeling optimization with wet‐lab practices that significantly enhance target metabolite titer through metabolic network engineering, offering a new route for constructing efficient cell factories for natural bioproducts.

A series of sulfonium, selenonium, and ammonium salts featuring diverse benzylidene acetal side chain substituents are designed and synthesized. In contrast to the previous work, this study emphasized stereochemical inversion at the 3'-position and bioisosteric replacements at the sulfonium cationic center. In vitro α-glucosidase inhibition assays identified 20b, 20l, and 21b as potent inhibitors. In vivo, 20b (15.0 mg kg-1) reduced postprandial blood glucose levels in sucrose-loaded mice by 40.6% (15 min), 49.5% (30 min), and 43.6% (60 min), surpassing acarbose (20.0 mg kg- 1). Molecular docking of 20b with the N-terminal subunit of Maltase-Glucoamylase (ntMGAM) revealed an identical binding mode, where 3'-stereoinversion induced π-π stacking between the benzylidene acetal phenyl ring and Phe450 and electrostatic interactions between the ortho-nitro group and Asp203. Cytotoxicity assessments confirmed the favorable safety profile of selected compounds in normal cell lines. Enzyme kinetic studies demonstrated fully competitive inhibition of α-glucosidase by these sulfonium salts.

BACKGROUND & AIMS:Maternal high level of folate and low level of vitamin B12, namely "folate and vitamin B12 imbalance", has been found to be associated with metabolic disorders, such as gestational diabetes mellitus (GDM). The aims of this study were to explore the associations of maternal serum folate, vitamin B12 and their imbalance in early pregnancy with GDM, and to explore the potential mediation effects of the methionine cycle related metabolites on the above associations. METHODS:This nested case-control study (172 GDM case-control pairs) was conducted based on a prospective birth cohort. Serum concentrations of 5-methyltetrahydrofolate (5-MTHF), vitamin B12 and methionine cycle related metabolites [S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and Homocysteine (Hcy)] were detected. 5-MTHF (nmol/L)/vitamin B12 (pmol/L) times 1000 was calculated to indicate the imbalance status of folate and vitamin B12. Conditional logistic regression was performed to analyze the associations of 5-MTHF, vitamin B12 and their imbalance with GDM. The mediation effect models were applied to explore the mechanism. RESULTS:High serum level of 5-MTHF in early pregnancy was related to a higher risk of GDM (OR = 2.00, 95%CI: 1.19-3.37). Compared with the group of the lowest tertile concentration of vitamin B12, the group of the highest concentration had a lower risk of GDM (OR = 0.33, 95%CI: 0.11-0.97). Higher 5-MTHF/vitamin B12 was associated with a higher risk of GDM (OR = 1.67, 95%CI: 1.08-2.56). Besides, no significant mediation effect of methionine cycle related metabolites was found on the associations of folate, vitamin B12 and the imbalance status with the risk of GDM. CONCLUSIONS:High maternal serum folate, low vitamin B12 levels and the resulting imbalance may increase the risk of GDM. The theory of "folate trap" could not explain the effect of folate, vitamin B12 and their imbalance on GDM.

Presented herein is the chemical construction of unprecedented 3,4-trans-3,6-anhydro hexofuranose frameworks. The disfavored 3,6-anhydro hexofuranosides were effectively established by Pd-catalyzed debenzylative intramolecular acetalation for the first time. The critical roles of benzyl protection and Pd as catalyst were demonstrated. Various 3,4-trans-3,6-anhydro sugars including sauropunol E was first obtained in satisfactory yields. Pharmaceutical investigation of the sauropunol E and its analogues revealed their potential application as anti-inflammatory agents.

Src homology-2 (SH2) domain-containing phosphatase-2 (SHP2) plays a crucial role in multiple cellular processes and is implicated in various human diseases. While most SHP2 inhibitors under development primarily target cancer, their potential in inflammatory diseases remains largely unexplored. In this study, we identified a novel series of benzoazepinamine-based SHP2 allosteric inhibitors. Notably, lead compound 6 demonstrated potent SHP2 inhibitory activity and significantly suppressed the production of key inflammatory mediators in the LPS-stimulated macrophages. Mechanistic studies revealed that 6 blocked the NF-κB pathway and inhibited the M1 macrophage polarization. Furthermore, compound 6 exhibited favorable pharmacokinetic properties and an acceptable toxicity profile. In vivo studies confirmed its therapeutic efficacy in reducing inflammation in both sepsis and acute lung injury mouse models. Together, these findings highlight SHP2 inhibition by compound 6 as a promising strategy for the treatment of inflammatory diseases.

Brain diseases have become an important health problem worldwide, especially in the aging population, and their incidence and prevalence continue to increase. Despite remarkable progress in medical technology, the treatment of brain diseases still faces many challenges, especially limitations caused by the blood-brain barrier (BBB), which significantly hinders the delivery of therapeutic drugs to the brain. In recent years, non-viral nanocarriers developed by nanotechnology have shown great potential for crossing the BBB, and have attracted much attention due to their low immunogenicity, high biocompatibility and good targeting. In this paper, we review the basic structure of the BBB, properties of nonviral vectors, and the mechanisms of crossing BBB. Moreover, this review summarizes the main types of non-viral vectors-liposomes, polymeric nanoparticles, biomimetic materials, and inorganic nanomaterials-while addressing the main translational barriers, including low BBB permeability, poor systemic stability, nonspecific peripheral accumulation, manufacturing challenges, and limited clinical validation, and suggests future research directions.