Heteromeric amino acid transporters (HATs), formed by the assembly of solute carrier 3(SLC3) and solute carrier 7(SLC7) family members, play essential roles in amino acid transmembrane transport, cellular nutrient sensing, and redox homeostasis. Dysregulation of multiple HATs members has been closely associated with tumor metabolic reprogramming, ferroptosis resistance, and inherited amino acid metabolic disorders, making them important targets for drug development. However, the high conservation of substrate-binding pockets, the limited druggability of zwitterionic compounds, and safety concerns arising from their broad expression in normal tissues have collectively hindered the clinical translation of HATs-targeted therapeutics. Recent advances in cryo-electron microscopy (Cryo-EM) have enabled the determination of high-resolution structures of multiple HATs, providing a critical foundation for understanding their molecular mechanisms and for guiding targeted interventions. These structural studies have systematically revealed the molecular basis of selective substrate recognition and ion coupling among different family members and have identified non-conserved structural features that may serve as potential opportunities for subtype-selective targeting. In this review, we systematically summarize recent advances in the structural biology of HATs, with a particular emphasis on their assembly mechanisms, substrate recognition modes, and conformational transitions. Furthermore, we highlight recent progress in structure-based drug design (SBDD), including strategies to enhance ligand affinity by exploiting non-conserved hydrophobic side pockets, as well as approaches to block the transport cycle by disrupting the secondary structures of transmembrane helices TM3 and TM10. Collectively, these insights provide an important structural framework and new perspectives for the development of highly selective inhibitors for HATs and related therapeutic strategies.
This study aimed to determine the conditions for establishing a zebrafish migraine model and to evaluate the therapeutic effects of Tianshu Capsules against migraine. A behavioral monitoring system was used to assess changes in zebrafish locomotor activity following nitroglycerin injection. Dopamine (DA) concentrations in zebrafish brain tissues were measured using an enzyme-linked immunosorbent assay (ELISA), and the mRNA expression levels of il-1b, nos2b, c-fos, and c-jun were determined by quantitative polymerase chain reaction (qPCR). Hematoxylin and eosin (HE) staining was performed to evaluate inflammatory changes in zebrafish brain tissues. These assessments were used to determine the conditions for establishing the zebrafish migraine model. After the model was established, zebrafish were assigned to Tianshu Capsules treatment groups. Changes in locomotor behavior and brain tissue biomarkers were evaluated to investigate the pharmacodynamic effects of Tianshu Capsules and further validate the model. The results showed that the locomotor velocity of zebrafish increased significantly after intraperitoneal injection of a 500 u03BCg/mL nitroglycerin solution (Pu0026lt; 0.01). Brain tissue DA levels decreased significantly (Pu0026lt;0.01), the mRNA expression levels of il-1b, nos2b, c-fos, and c-jun were upregulated, and inflammatory cell infiltration increased, indicating that the zebrafish migraine model was successfully established. Treatment with Tianshu Capsules reduced the locomotor distance and velocity of zebrafish following nitroglycerin injection (Pu0026lt;0.001) and significantly decreased the mRNA expression level of il-1b in brain tissues (Pu0026lt;0.01). It also showed a tendency to reduce the mRNA expression levels of nos2b, c-fos, and c-jun. HE staining showed that inflammatory cell infiltration in zebrafish brain tissues was reduced after treatment with Tianshu Capsules compared with that in the model group. These findings demonstrate that a zebrafish migraine model can be successfully established by nitroglycerin injection and that Tianshu Capsules exert therapeutic effects in this model, thereby further supporting the validity of the model. This study provides a useful tool for the high-throughput screening of antimigraine drugs.
In recent years,China's capacity for new drug research and development has been significantly strengthened,with major breakthroughs across multiple therapeutic areas,including cancer,autoimmune diseases,and metabolic disorders.An increasing number of domestically developed innovative drugs have been approved for marketing,gradually establishing a competitive position against imported drugs and expanding into global markets.This article systematically reviews the latest research progress of Class 1 innovative drugs in China from 2023 to 2024,categorizes representative approved drugs by therapeutic area,summarizes the clinical advantages and characteristics of representative drugs approved,analyzes in depth the current development trends of and challenges for China's innovative pharmaceutical industry,and explores future directions,aiming to provide some reference for innovative drug research,industrial development,and policy-making in China.
Chemical constituents of n-butanol fraction of ethanol extract from the leaves of Cyclocarya paliurus(Batalin)Iljinskaja were studied.Ten compounds were purified by silica gel,MCI,ODS,Sephadex LH-20 column chromatography and semi-preparative high-performance liquid chromatography.Based on the physicochemical properties and spectroscopic data,these compounds were identified as(4S)-4,8-dihydroxy-α-tetralone-5-[6'-(3",5"-dimethoxy-(E)-p-coumaroyl)]-β-D-glucopyranoside(1),(4S)-4,8-dihydroxy-α-tetralone-5-[6'-(E)-feruloyl]-β-D-glucopyranoside(2),(1S,3R,4S,5R)-4,5-di-O-caffeoyl quinic acid methyl ester(3),(1R,3R,4S,5R)-3,4-di-O-caffeoyl quinic acid methyl ester(4),(3R,5R)-3,4,5-tri-O-caffeoylquinic acid methyl ester(5),(1R,3R,4S,5R)-3-O-caffeoyl-5-O-p-coumaroyl quinic acid methyl ester(6),(1R,3R,4S,5R)-3-O-p-coumaroy-4-O-caffeoyl quinic acid methyl ester(7),(1R,3R,4S,5R)-3-O-caffeoyl-4-O-p-coumaroy quinic acid methyl ester(8),(3R,5R)-3,5-di-O-caffeoyl quinic acid methyl ester(9)and(1S,3R,4R,5R)-4-O-caffeoyl-5-O-feruloyl quinic acid methyl ester(10).Among them,compound 1 was a new compound,and compounds 3-10 were isolated from the genus C yclocarya for the first time.
This study aimed to elucidate the protective effect and underlying mechanism of epigallocatechin gallate(EGCG)against high glucose-induced pancreatic β-cell developmental anomalies in zebrafish.Zebrafish embryos were exposed to 2%glucose to induce abnormal pancreatic β-cell development and were pretreated with 10 μmol/L or 50 μmol/L EGCG.Mortality and body length were recorded;and the expression of key genes related to pancreatic β-cell development and function of pancreatic β-cells was detected by RT-PCR.The morphology of pancreatic β-cells in Tg(ins:mCherry)zebrafish was examined under a fluorescent microscope;and glucose levels,as well as the activities of superoxide dismutase(SOD),glutathione peroxidase(GPx),catalase(CAT),and the levels of malondialdehyde(MDA)and reactive oxygen species(ROS),were measured using commercial kits.The results showed that high-glucose treatment led to an increased mortality rate and body length in zebrafish larvae,along with sustained downregulation in the expression of transcription factors r egulating β-cell development.The expression of the insulin a gene(insa)initially increased and then decreased.High-glucose treatment also induced an increase in pancreatic fragmentation and hollow malformations,enlarged islet area,and elevated glucose levels in the body.Furthermore,it caused abnormal activities of SOD,GPx,and CAT enzymes,along with a significant rise in MDA and ROS content in zebrafish larvae.However,intervention with 50 μmol/L EGCG significantly reversed these abnormalities,restored normal β-cell morphology and function,and notably improved the oxidative stress status.In conclusion,EGCG significantly ameliorates high glucose-induced abnormal development of pancreatic β-cells in zebrafish,and its mechanism may be related to the improvement of oxidative stress and glucose levels in zebrafish.
Molecular glue drugs exert pharmacological effects by inducing or stabilizing protein-protein interactions.Evaluating their activity not only requires assessing their binding to proteins,but also involves the evaluation of multiple aspects such as ternary complex formation,interface stability,cooperativity,and intracellular function.This review summarizes the commonly used methods and applications for evaluating the activity of molecular glues from three aspects:in vitro quantitative detection,cellular validation,and theoretical calculations and simulations;and proposes a hierarchical approach to activity evaluation based on the actual needs for efficiency in drug development,aiming to provide some reference for the study of molecular glue drug activity and the selection of evaluation methods.
This study aimed to investigate the mechanism of liquiritin(LQ)in the improvement of ventricular remodeling(VR)after acute myocardial infarction(AMI).Molecular docking was used to predict the binding affinity of liquiritin to thioredoxin-interacting protein(TXNIP).After 2 weeks of modeling,the rats were randomly divided into a model group,a low-dose liquiritin group(20 mg/kg LQ),and a high-dose liquiritin group(40 mg/kg LQ).Liquiritin was administered by gavage once a day,and the sham group and model group were g iven the same volume of 0.5%sodium carboxymethylcellulose(CMC-Na),with intervention of 4 consecutive weeks.Echocardiography was employed to detect the cardiac function,HE staining was used to observe cardiological changes,ELISA was used to detect the activity of serum creatine kinase-MB(CK-MB)activity,and the colorimetric method was adopted to detect serum malondialdehyde(MDA),total superoxide dismutase(T-SOD)and catalase(CAT)activities.RT-qPCR was used to detect the gene expressions of TXNIP,thioredoxin(TRX)and NACHT,LRR,and PYD domains-containing protein 3(NLRP3).Western blot was used to detect the protein expressions of TXNIP,TRX and NLRP3 in rat myocardial tissue.Molecular docking results showed that liquiritin had a good binding affinity to TNXIP target.After 20 and 40 mg/kg liquiritin intervention,the levels of ejection fraction(EF)and fractional shortening(FS)were significantly increased(P<0.01),and the levels of LVIDs,LVIDd,LVESV,and LVEDV were decreased(P<0.01).The myocardial structure was significantly improved,the cell arrangement tended to be regular,and the area of inflammatory cell infiltration and necrosis was reduced.Liquiritin significantly reduced the level of CK-MB(P<0.01),decreased the activity of MDA,and increased the activities of CAT and T-SOD(P<0.01).Liquiritin effectively inhibited the overexpression of TXNIP and NLRP3 genes and proteins,and enhanced the expression of TRX genes and proteins in the myocardial tissues of AMI rats.In conclusion,liquiritin has a regulatory effect on the TXNIP/TRX signaling pathway,inhibits the activation of the NLRP3 inflammasome,and thus improves ventricular remodeling after acute myocardial infarction.
To address the constrains imposed by insufficient hydrogen peroxide(H2O2)and high glutathione(GSH)expression in tumor cells on the efficacy of chemodynamic therapy(CDT),zeolitic imidazolate framework-8(ZIF-8)loaded with disulfiram(DSF)and 3-amino-1,2,4-triazole(3-AT)was synthesized via a one-pot approach.Subsequently,hyaluronic acid(HA)-modified cupric peroxide(CuO2)was in-situ grown on its surface through biomineralization to construct a multifunctional copper-based nanozyme ADZCH(3-AT/DSF@ZIF-8@CuO2-HA).This nanoplatform disrupts the intratumoral H2O2 homeostasis,depletes GSH,and synchronously delivers DSF and Cu2+via cascade catalysis,thereby enhancing CDT and sensitizing tumors to DSF-based chemotherapy.The results of physicochemical characterization indicated that ADZCH presented a uniform core-shell structure with favorable dispersibility.Its particle size and Zeta potential were 196.5 nm and-19.5 mV,respectively.It possessed a microporous structure with a specific surface area of 81.860 0 m2/g,and demonstrated efficient loading capacity for DSF and 3-AT,achieving drug loading efficiencies of 5.91%and 45.07%,respectively.Moreover,ADZCH can continuously and slowly release drugs in an acidic environment and maintain good stability under diverse physiological conditions.In vitro functional assays verified that ADZCH catalytically generated H2O2 and hydroxyl radicals while concurrently depleting GSH in a concentration-and incubation time-dependent manner.Cellular uptake experiments showed that HA modification significantly improved the uptake of nanoparticles by 4T1 cells.Cytotoxicity tests showed that 80 μg/mL ADZCH had a significant cytotoxic effect on 4T1 cells but no significant toxicity on L929 cells.DCFH-DA probe detection indicated that ADZCH could significantly induce intracellular reactive oxygen species(ROS)generation,thereby enhancing CDT efficacy.Live/dead staining experiments showed that ADZCH efficiently induced apoptosis,with the proportion of dead cells reaching 94.74%,demonstrating its promising potential for anti-tumor applications.This study provides new research ideas and experimental basis for overcoming the tumor microenvironment barrier and enhancing the anti-tumor effect of CDT combined with chemotherapy.
Cardiotoxicity induced by antineoplastic agents is an important factor affecting the prognosis of cancer patients.This article systematically summarizes the clinical manifestations of cardiotoxicity caused by chemotherapeutic drugs,molecular targeted cancer therapies,and immunotherapeutic drugs,and identifies the core injury mechanisms,including cardiomyocyte apoptosis,oxidative stress,and mitochondrial dysfunction.In Traditional Chinese Medicine(TCM)theory,anticancer drug-induced cardiotoxicity falls under the category of"heat toxins"characterized by dual deficiency of qi and blood,upward flaming of heart heat,stagnation of the heart vessels,and meridian obstruction induced by phlegm-dampness.Therefore,by reviewing the preventive and therapeutic effects and the underlying mechanisms of tonic medicines,interior heat-clearing medicines,blood-circulating and stasis-resolving medicines,phlegm-transforming,cough-suppressing and panting-relieving medicines,and interior-warming medicines,this paper concludes that TCM prevention and treatment of this condition adheres to the formulation principle of"reinforcing healthy qi,removing toxins,and resolving blood stasis".Its mechanisms of action—including antioxidation effects,regulation of autophagic balance,antagonism of inflammatory responses,and improvement of microcirculation—are highly consistent with modern medical treatment strategies(e.g.,dexrazoxane f or inhibiting iron-dependent oxidative stress,statins for anti-inflammatory effects).This study provides theoretical support and practical guidance for the collaborative and precise prevention and treatment of anticancer drug-induced cardiotoxicity through the integration of traditional Chinese and Western medicine.
3CL protease(3CLpro)of SARS-CoV-2 is a pivotal enzyme required in coronavirus replication and transcription.Its highly conserved structure and the absence of homologous proteins in the host make it an ideal target for broad-spectrum anti-coronavirus drug development.In this work,we systematically investigated and compared the binding modes and dynamic properties of the four stereoisomers of a pyridyl-urea diyne ester(PyDU)molecule with two chiral centers within the 3CLpro active site.Through molecular docking,MD simulations,MM/GBSA binding free-energy calculations,and DCCM analysis,all four stereoisomers were stabilized primarily by hydrophobic packing.Among them,the(R,S)isomer exhibited the best overall performance,including docking score,binding free-energy components,and key residue interactions.The(R,S)and(S,R)isomers also enhanced the cooperative motions around the binding pocket,while the(R,S)isomer f urther modulated the flexibility of domain Ⅲ,which may influence 3CLpro dimerization.Conversely,the(S,S)isomer exhibited the weakest affinity due to insufficient hydrophobic contact.By innovatively integrating chirality,binding energy and protein dynamical features,we revealed the dual role of chirality in modulating affinity and dynamic responses,which provides a theoretical basis for the chiral-guided design of coronavirus inhibitors.
To investigate the effect of mesenchymal stromal cells(MSCs)on the fibrosis progression and endometrial regeneration in mouse models of endometrial injury,a mouse endometrial injury model was established by physical scraping combined with lipopolysaccharide(LPS)chemical induction,and the endometrium morphology and collagen deposition were evaluated by HE and Masson staining after unilateral administration of MSCs.RT-qPCR and immunofluorescence were used to detect the expression of epithelial markers Epcam and collagen I(Col1).Primary endometrial epithelial cells were isolated to assess p21 expression.Fibrosis-related genes and signaling pathways were validated using transcriptome sequencing and RT-qPCR.The experimental results showed that MSCs increased endometrial thickness and number of glands(P<0.05),up-regulated the expression of Epcam(P<0.01),while significantly reducing uterine collagen fiber deposition(P<0.05)and the expression of p21 in primary epithelial cells(P<0.000 1).Transcriptomic analysis revealed that MSCs attenuated collagen deposition by modulating genes involved in the TGF-β signaling pathway.This study elucidates that MSCs facilitate uterine repair by reversing endometrial fibrosis and promoting epithelial regeneration,and their role is related to the regulation of the TGF-β/SMAD pathway and suppression of aberrant c ollagen accumulation.
Sixteen compounds were isolated from the solid rice culture of the endophytic fungus Alternaria alstroemeriae WZ-419 derived from Pseudostellariae Radix,using silica gel,ODS,Sephadex LH-20 column chromatography,and preparative HPLC.Their structures were elucidated based on physicochemical properties and comprehensive spectroscopic analyses,and identified as alterpenoid A(1),tricycloalternarene A(2),altenusin(3),4'-epialtenuene(4),altenuene(5),alternariol(6),altenuisol(7),3-hydroxyalternariol-5-O-methylether(8),alternariol-9-methyl ether(9),alternariol 1'-hydroxy-9-methyl ether(10),stemphyperylenol(11),dihydroalterperylenol(12),alterinone A(13),4-hydroxy-3-methoxy-5-(2E,6E-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)benzoic acid(14),hexylitaconic acid(15),and altechromone A(16).Among them,compound 1 and 13 were new,and compounds 14 and 15 were isolated from the genus Alternaria for the first time.The antibacterial a ctivities of compounds 1-16 were evaluated in vitro.Compounds 3,6-8,10,11,13,and 14 exhibited notable inhibitory effects against Gram-positive bacteria,with minimal inhibitory concentrations ranging from 8 to 64 µg/mL.This study isolated a series of antimicrobial metabolites from the endophytic fungi of Pseudostellariae Radix,providing new insights into their bioactive constituents and laying a foundation for further pharmacological investigations.
In this study, the synthetic process of 18u03B1-glycyrrhizic acid was optimized. Using 18u03B2-glycyrrhizic acid monoammonium salt as the starting material, the target compound 18u03B1-glycyrrhizic acid was obtained through isomerization, esterification, and hydrolysis, with a total yield of 9.43%, purity of 99.23% and key impurity A of 0.17% (HPLC). The optimized process significantly improved the isomerization conversion rate, reduced the formation of related substances, simplified the purification steps, and enhanced both industrial scalability and cost efficiency.
This study aimed to design and synthesize a series of novel photocaged compounds based on the precise binding mode of cyclin-dependent kinase 2(CDK2)inhibitor AT7519 with its target,to achieve precise optical control over molecular activity.Using AT7519 as the structural foundation,different types of photoremovable protecting groups were introduced at its key interaction sites(the NH of the pyrazole ring and the NH of the piperidine ring),resulting in the synthesis of eight dual-photocaged compounds.Their structures were confirmed by NMR and mass spectrometry,and their photochemical properties—including photolysis wavelength,photolysis time,and photolysis efficiency—were systematically evaluated.The optically controlled inhibitory effects of the compounds on HCT116 cell proliferation were assessed using MTT assay.The photoresponsive characteristics of the photocaged compounds were significantly influenced by the type of photoremovable protecting group and its introduction site.Among them,compounds 1a,1b,and 2d exhibited excellent photolysis efficiency,each achieving a rate exceeding 90%.Particularly,compounds 1b and 2d d emonstrated excellent optically controlled activity:under dark conditions,their half maximal inhibitory concentration(IC50)values were both greater than 150 µmol/L,indicating negligible cell proliferation inhibitory activity;however,upon irradiation,their cell proliferation inhibitory activity significantly increased,with IC50 values comparable to those of the positive control AT7519.The obtained compounds 1b and 2d possess excellent optically controlled properties,and can be further investigated as potential candidates for optically controlled CDK2 inhibitors.
This study systematically examined the effects of atomization as a transdermal permeation enhancer on the transdermal delivery of active ingredients with different physicochemical properties and investigated the underlying mechanisms.Porcine ear skin served as an in vitro model,and skin permeation experiments were conducted using Franz diffusion cells.Receptor fluids were collected at specific time points,and samples of the stratum corneum and viable epidermis-dermis were separated and prepared.Quantitative and visualization methods,including high-performance liquid chromatography,fluorescence derivatization,and confocal laser scanning microscopy,were used to compare skin retention and transdermal permeation of adenosine(AD),tranexamic acid(TXA),calcein(CAL),and tocopheryl acetate(TA)under atomized and non-atomized conditions.Additionally,transepidermal water loss(TEWL)measurements and attenuated total reflectance-Fourier transform infrared spectroscopy(ATR-FTIR)were employed to analyze the mechanism behind the penetration enhancement caused by atomization.The findings showed that atomization increased skin r etention within the stratum corneum and viable epidermis-dermis,as well as the transdermal permeation of all four active ingredients to varying degrees.The most significant enhancement was observed for TXA,which has a relatively low molecular weight and moderate lipophilicity,while the enhancement effects for highly hydrophilic AD and highly lipophilic TA were comparatively limited;however,atomization significantly increased the skin retention of TA.TEWL results indicated that skin permeability increased within 4 hours after atomization and largely recovered within 8 hours.ATR-FTIR analysis suggested that atomization may facilitate transdermal delivery by disrupting the lipid order and keratin conformation in the stratum corneum.This study provides theoretical support and experimental references for the advancement of atomization transdermal delivery technology,as well as the design and development of related atomization products.
Exportin 1(XPO1)is aberrantly overexpressed in various malignant tumors and can lead to the loss of anti-tumor effects of important tumor suppressor proteins such as p53,RB1,and FOXO by mediating their nuclear export.Although XPO1 inhibitor Selinexor has entered clinical application,its single-agent anti-tumor activity remains suboptimal,which is closely related to the compensatory activation of multiple signaling pathways in response to XPO1 inhibition.Focusing on the core regulatory role of XPO1 in tumor cells,this article systematically summarizes the current landscape of combination therapies involving XPO1 inhibitors and various targeted agents,including inhibitors of CDK4/6,FLT3,BET,ATR,and BCL2/MDM2,aiming to provide some reference for the development of XPO1-centered combination therapy strategies.
This study aimed to establish an analytical method capable of simultaneously quantifying the prototype components of Si-Ni-San and screening their metabolites to elucidate its tissue distribution and metabolic characteristics in an ulcerative colitis(UC)mouse model.To this end,an integrated analysis strategy based on UPLC-QqQ-MS was developed and validated,combining the targeted quantification of 12 prototype c omponents with a pseudo-targeted metabolite screening technique based on ion pair list-triggered data-dependent acquisition.Samples were extracted with 80%methanol(100 mg/mL)and processed with internal standards.Separation was achieved on a Waters Acquity UPLC HSS PFP column using a gradient elution with a mobile phase consisting of acetonitrile and 5 mmol/L ammonium acetate containing 0.1%formic acid.Analysis was performed using an electrospray ionization(ESI)source in multiple reaction monitoring mode.Methodological validation confirmed that all parameters met the requirements for bio-sample analysis.Application of this method revealed that the content of Si-Ni-San prototype components in the colon,liver,and kidneys of UC mice was significantly higher than that in healthy mice.Furthermore,the number of phase Ⅱ metabolites was markedly greater than that of phase Ⅰ metabolites in all tested samples.The results demonstrate the reliability of the established method and preliminarily reveal the tissue distribution characteristics of Si-Ni-San under UC conditions and its metabolism pattern dominated by phase Ⅱ conjugation,which provides a methodological basis and experimental data for further in-depth research into its effective target tissues and pharmacodynamic material basis.
As an important strategy in antiviral drug development,nucleoside analogs(NAs)have attracted considerable attention due to their unique mechanisms of action and favorable safety profile.This review systematically summarizes recent advances in the mechanisms of action of NAs,focusing on the following four aspects:(1)Targeting viral polymerases,inhibiting viral replication through mechanisms such as non-absolute termination,delayed chain termination and induction of viral RNA mutations in addition to classical chain termination,which has been newly discovered;(2)Regulating RNA methylation modifications—for instance,competitively inhibiting methyltransferases,which significantly reduces viral replication efficiency;(3)Depleting nucleotide pools—by affecting host cell purine nucleotide synthesis pathways,thereby indirectly inhibiting viral replication;and(4)Immunomodulatory functions—including activation of the STING pathway to promote interferon production.Furthermore,this review systematically discusses the breakthrough progress in prodrug technologies for addressing key clinical challenges such as drug resistance and off-target toxicity of NAs.These advances provide crucial technical support for the clinical translation of NAs.These advances provide key technical support for the clinical translation of NAs.This review clarifies the multi-target action rules of NAs and provides a theoretical framework for the design of next-generation broad-spectrum antiviral agents.
This study aimed to analyze research hotspots as well as domestic and international collaboration trends in the field of pharmacology and toxicology in China.Articles published in this field between 2005 and 2024 by Chinese researchers were retrieved and analyzed using citation analysis and descriptive statistical methods.The results indicate that over the past two decades,China's level of international collaboration in this field has been continuously improving.China cooperates most closely with the United States,while its collaboration with other countries remains relatively limited.However,China's cooperation with Belt and Road Initiative((BRI)partner countries has gradually deepened.The influence of Chinese publications in pharmacology and toxicology over the past 20 years is comparable to the global average.Papers resulting from international collaboration exceed the global average in terms of the impact,whereas those based solely on domestic collaboration still have significant room for improvement.It is recommended that China adhere to the principle of"coordinating well for comprehensive advancement"in international cooperation,strengthen collaborative relationships with various countries,and uphold the'self-directed'approach to enhance the global influence of the discipline.Furthermore,optimizing the layout of international research collaboration networks,promoting innovation in research models,and leveraging the advantages of a diversified funding system are essential to overcome existing spatial and technological limitations.
Hepatitis B virus(HBV)infection represents a significant global health challenge.Current therapeutic options,such as interferon and nucleoside analogues(NAs),are limited by issues including long-term medication toxicity,the virus's propensity to develop drug resistance,and the inability to eradicate covalently closed circular DNA(cccDNA).Core protein allosteric modulators(CpAMs),as an emerging class of anti-HBV drugs,target HBcAg to interfere with capsid assembly.This not only blocks viral nucleocapsid formation and inhibits viral replication but also indirectly destabilizes the cccDNA pool,while exhibiting a relatively high genetic barrier to resistance.This article systematically evaluates HBV drug resistance to CpAMs and proposes anti-resistance strategies,including the combination of nucleoside analogues with CpAMs,enhancing protein-drug interactions,targeting HBcAg degradation,designing multi-target inhibitors,and employing combination therapy.Looking ahead,the integration of structural biology,computational chemistry,and immunotherapy will offer innovative approaches for developing novel,highly effective,and low-resistance inhibitors,thereby advancing the functional cure of hepatitis B.
