Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the devel...Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols(P),targeted drugs(T),and metal ions(M),collectively referred to as PTM regimens.The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.Methods:The effects of the pharmaceutical agents on the proliferation of cultured cancer cells and pathogens were assessed after 72 h and 48 h,respectively,using the MTT(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide)assay and optical density at 600 nm(OD600).The synergistic effects of drug combinations were evaluated by combination index(CI),where CI<1 indicates synergism,CI=1 indicates addition,and CI>1 indicates antagonism.Efficacy index(EI)was also calculated.Assays of efflux pump ATPase activities were conducted using a colorimetric method.Results:This study evaluated the anticancer and antibacterial efficacy of PTM regimens that included phytopolyphenols(specifically curcumin(C)and green tea polyphenols(G)),repurposed drugs(memantine(Mem),thioridazine(TRZ),cisplatin(Cis),and 5-fluorouracil(5FU)),and ZnSO_(4)(Zn)across three cultured cancer cell lines and four cultured pathogens.The most effective regimens,GC·Mem·Zn and GC·TRZ·Zn,significantly enhanced the anticancer efficacy(EI)of cisplatin across the three cancer lines(OECM-1,A549 and DLD-1)by 7,11 and 21;7,9,and 17 fold,respectively,while the enhancements for 5-fluorouracil were 5,6 and 12;5,5 and 9 fold,respectively.Furthermore,these PTM regimens demonstrated substantial synergistic inhibition of Na^(+)-K^(+)-Mg^(2+)-ATPase and Mg^(2+)-ATPase in the cultured cancer cells,as well as a reduction in biofilm formation by the four cultured pathogens,suggesting their potential to address the challenges of multidrug resistance in cancers and infectious diseases.Conclusion:Given that all drugs incorporated in the PTM regimens have been clinically validated for safety and efficacy,particularly regarding their synergistic selective anticancer efficacy,inhibition of efflux pump ATPase,and antibiofilm formation of pathogens,these regimens may offer a promising therapeutic strategy to alleviate the severe side effects and drug resistance typically associated with chemotherapeutic agents.Further preclinical and clinical investigations are warranted.展开更多
Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challengin...Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.展开更多
Structure-based virtual screening utilizing the approved drugs is an intriguing and laudable approach to excavate novel alternatives for different indications based on the vast amount of reported experimental data.Vir...Structure-based virtual screening utilizing the approved drugs is an intriguing and laudable approach to excavate novel alternatives for different indications based on the vast amount of reported experimental data.Virus superfamily 1 helicase could resolve hydrogen bonds between base pairs and participate in nucleic acid replication and has emerged as a potential target for managing virus infection.Nonetheless,current drug exploitation targeting viral helicases is still in infancy.This work establishes an intelligent multi-computational screening programme to screen potential inhibitors targeting tobacco mosaic virus(TMV)helicase using Food and Drug Administration(FDA)-approved commercially available molecule library.The ranked top 6 hits were further validated by root mean square deviations/fluctuations(RMSD/F),molecular mechanics Poisson Boltzmann surface area(MM-PBSA),density functional theory(DFT)calculations,and bioactivity evaluation.Encouragingly,lumacaftor(ΔE_(total)=-29.0kcal/mol,K_(d)=0.22μmol/L,half maximal inhibitory concentration(IC_(50))=162.5μmol/L)displayed superior binding strength and enzyme inhibition against TMV helicase compared to ningnanmycin(K_(d)=9.35μmol/L,IC_(50)>200μmol/L).Therefore,lumacaftor may be able to inhibit TMV replication by binding to helicase and interfering with its biofunctionability.Besides,the lumacaftor-helicase binding mode changes from H-bonding/electrostatic interactions to hydrophobic interactions in trajectory analysis.Overall,current findings suggest this state-of-the-art stratagem is fruitful and has the potential to be engaged in rapid mining of other target inhibitors for disease treatment.展开更多
Colorectal cancer(CRC)ranks as the third most common cancer globally and the second leading cause of cancer-related deaths,representing a significant health burden.Despite advancements in traditional treatments such a...Colorectal cancer(CRC)ranks as the third most common cancer globally and the second leading cause of cancer-related deaths,representing a significant health burden.Despite advancements in traditional treatments such as surgery,chemotherapy,targeted therapy,and immunotherapy,these approaches still face challenges,including high costs,limited efficacy,and drug resistance.Drug repurposing has emerged as a promising strategy for CRC treatment,offering advantages with reduced development timelines,lower costs,and improved drug accessibility.This review explores drug repurposing strategies for CRC,supported by multidisciplinary technologies,and discusses the current challenges in the field.展开更多
Drug repurposing offers a promising alternative to traditional drug development and significantly re-duces costs and timelines by identifying new therapeutic uses for existing drugs.However,the current approaches ofte...Drug repurposing offers a promising alternative to traditional drug development and significantly re-duces costs and timelines by identifying new therapeutic uses for existing drugs.However,the current approaches often rely on limited data sources and simplistic hypotheses,which restrict their ability to capture the multi-faceted nature of biological systems.This study introduces adaptive multi-view learning(AMVL),a novel methodology that integrates chemical-induced transcriptional profiles(CTPs),knowledge graph(KG)embeddings,and large language model(LLM)representations,to enhance drug repurposing predictions.AMVL incorporates an innovative similarity matrix expansion strategy and leverages multi-view learning(MVL),matrix factorization,and ensemble optimization techniques to integrate heterogeneous multi-source data.Comprehensive evaluations on benchmark datasets(Fdata-set,Cdataset,and Ydataset)and the large-scale iDrug dataset demonstrate that AMVL outperforms state-of-the-art(SOTA)methods,achieving superior accuracy in predicting drug-disease associations across multiple metrics.Literature-based validation further confirmed the model's predictive capabilities,with seven out of the top ten predictions corroborated by post-2011 evidence.To promote transparency and reproducibility,all data and codes used in this study were open-sourced,providing resources for pro-cessing CTPs,KG,and LLM-based similarity calculations,along with the complete AMVL algorithm and benchmarking procedures.By unifying diverse data modalities,AMVL offers a robust and scalable so-lution for accelerating drug discovery,fostering advancements in translational medicine and integrating multi-omics data.We aim to inspire further innovations in multi-source data integration and support the development of more precise and efficient strategies for advancing drug discovery and translational medicine.展开更多
Gastric cancer(GC)is both the fifth most common cancer worldwide and the fifth in mortality.Owing to a lack of symptoms in the early stages and unspecific cli-nical presentation in the later stages,GC is usually diagn...Gastric cancer(GC)is both the fifth most common cancer worldwide and the fifth in mortality.Owing to a lack of symptoms in the early stages and unspecific cli-nical presentation in the later stages,GC is usually diagnosed at advanced stages.This means that only approximately 60%of patients are eligible for curative treat-ment,and overall,GC patients have a 5-year survival rate of only 28.3%,under-scoring the importance of developing new treatment strategies.Drug repurposing involves identifying new therapeutic uses for approved drugs and is a promising strategy for cancer treatment because of its lower cost and faster development time.A variety of targetable pathways are involved in GC progression,including the mitogen-activated protein kinase,phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin,p53,Janus kinase 2/signal transducer and activator of transcription 3,hypoxia-inducible factor-1α,wingless-type mouse mammary tumor virus integration site family/beta-catenin(Wnt/β-catenin),nuclear factor kappa B,and Hippo pathways.Therefore,the repurposing of drugs targeting these pathways represents an interesting option in the search for new treatments for GC.In this review,we explore some relevant pathways involved in the development of GC and the possibilities of repurposing drugs that target them.展开更多
The 2024 development of a precision-engineered retrotransposon system marked a significant milestone in mammalian genome-editing research.As appeared in the July 8 issue of Cell,this methodological breakthrough establ...The 2024 development of a precision-engineered retrotransposon system marked a significant milestone in mammalian genome-editing research.As appeared in the July 8 issue of Cell,this methodological breakthrough established a novel framework for site-specific gene delivery through repurposing ancient viral tools.展开更多
Protozoan infections(e.g.,malaria,trypanosomiasis,and toxoplasmosis)pose a considerable global burden on public health and socioeconomic problems,leading to high rates of morbidity and mortality.Due to the limited ars...Protozoan infections(e.g.,malaria,trypanosomiasis,and toxoplasmosis)pose a considerable global burden on public health and socioeconomic problems,leading to high rates of morbidity and mortality.Due to the limited arsenal of effective drugs for these diseases,which are associated with devastating side effects and escalating drug resistance,there is an urgent need for innovative antiprotozoal drugs.The emergence of drug repurposing offers a low-cost approach to discovering new therapies for protozoan diseases.In this review,we summarize recent advances in drug repurposing for various human protozoan diseases and explore cost-effective strategies to identify viable new treatments.We highlight the cross-applicability of repurposed drugs across diverse diseases and harness common chemical motifs to provide new insights into drug design,facilitating the discovery of new antiprotozoal drugs.Challenges and opportunities in the field are discussed,delineating novel directions for ongoing and future research.展开更多
Computational approaches,encompassing both physics-based and machine learning(ML)methodologies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA...Computational approaches,encompassing both physics-based and machine learning(ML)methodologies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA)transporter(hDAT)is the primary therapeutic target of numerous psychiatric medications.However,traditional hDAT-targeting drugs,which interact with the primary binding site,encounter significant limitations,including addictive potential and stimulant effects.In this study,we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape(WHALES)descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs.Initially,WHALES descriptors facilitated a similarity search,employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates.Consequently,from a compound library of 4,921 marketed and clinically tested drugs,we identified 27 candidate atypical inhibitors.Subsequently,ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates,while induced-fit docking(IFD)was performed to estimate their binding affinities.Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities.Among these,three exhibited significant inhibitory potency,with half maximal inhibitory concentration(IC_(50))values of 0.753μM,0.542μM,and 1.210μM,respectively.Finally,molecular dynamics(MD)simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation.In conclusion,our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.展开更多
Objective To improve the system of accelerated review and approval,and to speed up the development and marketing of repurposing drugs for rare diseases in China.Methods The relevant concepts of rare diseases and the d...Objective To improve the system of accelerated review and approval,and to speed up the development and marketing of repurposing drugs for rare diseases in China.Methods The relevant concepts of rare diseases and the definition of drug repurposing were introduced so as to sort out the advantages and disadvantages of the research and development of drug repurposing for rare diseases.Then,the incentive mechanisms of the research and development of drug repurposing for rare diseases in China and abroad were compared.Results and Conclusion Some suggestions on improving the incentive mechanism of repurposing drugs for rare diseases such as policy support for talents introduction,capital investment,and innovation capabilities are proposed.Besides,the government should further improve policies for the research and development of repurposing drugs for rare diseases,which can gradually narrow the gap between the research and innovation of drug repurposing in developed countries,thus benefiting the patients of rare diseases.展开更多
BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast ...BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast crisis chronic myeloid leukemia(BC-CML)is highly lethal.Advances in whole exome sequencing(WES)reveal pan-cancer mutations in BC-CML,supporting mutation-guided therapies beyond Breakpoint cluster region-Abelson.Artificial intelligence(AI)and machine learning(ML)enable genomic stratification and drug repurposing,addressing overlooked actionable mutations.AIM To stratify BC-CML into molecular subtypes using WES,ML,and AI for precision drug repurposing.METHODS Included 123 CML patients(111 CP-CML,5 AP-CML,7 BC-CML).WES identified pan-cancer mutations.Variants annotated via Ensembl Variant Effect Predictor and Catalogue of Somatic Mutations in Cancer(COSMIC).ML(principal component analysis,K-means)stratified BC-CML.COSMIC signatures and PanDrugs prioritized drugs.Analysis of variance/Kruskal-Wallis validated differences(P<0.05).RESULTS In this exploratory,hypothesis-generating study of BC-CML patients(n=7),we detected over 2500 somatic mutations.ML identified three BC-CML clusters:(1)Cluster 1[breast cancer susceptibility gene 2(BRCA2),TP53];(2)Cluster 2[isocitrate dehydrogenase(IDH)1/2,ten-eleven translocation 2];and(3)Cluster 3[Janus kinase(JAK)2,colony-stimulating factor 3 receptor],with distinct COSMIC signatures.Therapies:(1)Polyadenosinediphosphate-ribose polymerase inhibitors(olaparib);(2)IDH inhibitors(ivosidenib);and(3)JAK inhibitors(ruxolitinib).Mutational burden,signatures,and targets varied significantly across clusters,supporting precision stratification.CONCLUSION This WES-AI-ML framework provides mutation-guided therapies for BC-CML,enabling real-time stratification and Food and Drug Administration-approved drug repurposing.While this exploratory study is limited by its small sample size(n=7),it establishes a methodological framework for precision oncology stratification that warrants validation in larger,multi-center cohorts.展开更多
Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CR...Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC50 values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.展开更多
Over the course of the past 70 years, the objectives of CA （cellular automata） research shifted from speculative and illustrative purposes without immediate goals outside of given implementations to the more utilita...Over the course of the past 70 years, the objectives of CA （cellular automata） research shifted from speculative and illustrative purposes without immediate goals outside of given implementations to the more utilitarian scientific and engineering objectives of simulating, controlling and predicting other phenomena. Looking back at our own 10-year history of CA related work, however, we recognize a generally inverse tendency from utilitarian objectives to finding more illustrative and speculative value. In this paper, we present a reflection on our own body of CA work, and we discuss the qualities of the various outcomes and insights we gained from a second-order cybernetic perspective. We argue that much of our own CA work may best be understood as creating machines for showing and for repurposing that allow their observers to gain new （second-order cybernetic） ways of seeing from interacting with them.展开更多
In the last decade,attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system,as insulin in the brain is implicated in neuronal survival,pla...In the last decade,attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system,as insulin in the brain is implicated in neuronal survival,plasticity,oxidative stress and neuroinflammation.Diabetes mellitus and Parkinson’s disease are both aging-associated diseases that are turning into epidemics worldwide.Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson’s disease but can also determine the prognosis and progression of Parkinsonian symptoms.Today,there are no available curative or disease modifying treatments for Parkinson’s disease,but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson’s disease,both in diabetic and nondiabetic Parkinsonian patients.Furthermore,it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson’s disease.Here,we review the present evidence on the connection between Parkinson’s disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism,with a particular focus on glucagon-like peptide-1 receptor agonists.展开更多
Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.Ho...Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.However,there are still unmet needs for treating chronic HEV infections.Herein,we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds.Upon screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities.Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection.Pyrazofurin selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains.Encouragingly,both drugs exhibited a sizeable therapeutic window against HEV.For instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients.Mechanistically,their anti-HEV mode of action depends on the blockage of pyrimidine synthesis.Notably,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral activity.In conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections.Based on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.展开更多
Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies,such as chemotherapy,radiotherapy,and molecular targeted therapy.Immunotherapy has emerged as a promising t...Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies,such as chemotherapy,radiotherapy,and molecular targeted therapy.Immunotherapy has emerged as a promising therapeutic modality but the efficacy has plateaued,which therefore provides limited benefits to patients with cancer.Identification of more effective approaches to improve patient outcomes and extend survival are urgently needed.Drug repurposing has emerged as an attractive strategy for drug development and has recently garnered considerable interest.This review comprehensively analyses the efficacy of various repurposed drugs,such as transforming growth factor-beta(TGF-β)inhibitors,metformin,receptor activator of nuclear factor-κB ligand(RANKL)inhibitors,granulocyte macrophage colony-stimulating factor(GM-CSF),thymosinα1(Tα1),aspirin,and bisphosphonate,in tumorigenesis with a specific focus on their impact on tumor immunology and immunotherapy.Additionally,we present a concise overview of the current preclinical and clinical studies investigating the potential therapeutic synergies achieved by combining these agents with immune checkpoint inhibitors.展开更多
文摘Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols(P),targeted drugs(T),and metal ions(M),collectively referred to as PTM regimens.The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.Methods:The effects of the pharmaceutical agents on the proliferation of cultured cancer cells and pathogens were assessed after 72 h and 48 h,respectively,using the MTT(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide)assay and optical density at 600 nm(OD600).The synergistic effects of drug combinations were evaluated by combination index(CI),where CI<1 indicates synergism,CI=1 indicates addition,and CI>1 indicates antagonism.Efficacy index(EI)was also calculated.Assays of efflux pump ATPase activities were conducted using a colorimetric method.Results:This study evaluated the anticancer and antibacterial efficacy of PTM regimens that included phytopolyphenols(specifically curcumin(C)and green tea polyphenols(G)),repurposed drugs(memantine(Mem),thioridazine(TRZ),cisplatin(Cis),and 5-fluorouracil(5FU)),and ZnSO_(4)(Zn)across three cultured cancer cell lines and four cultured pathogens.The most effective regimens,GC·Mem·Zn and GC·TRZ·Zn,significantly enhanced the anticancer efficacy(EI)of cisplatin across the three cancer lines(OECM-1,A549 and DLD-1)by 7,11 and 21;7,9,and 17 fold,respectively,while the enhancements for 5-fluorouracil were 5,6 and 12;5,5 and 9 fold,respectively.Furthermore,these PTM regimens demonstrated substantial synergistic inhibition of Na^(+)-K^(+)-Mg^(2+)-ATPase and Mg^(2+)-ATPase in the cultured cancer cells,as well as a reduction in biofilm formation by the four cultured pathogens,suggesting their potential to address the challenges of multidrug resistance in cancers and infectious diseases.Conclusion:Given that all drugs incorporated in the PTM regimens have been clinically validated for safety and efficacy,particularly regarding their synergistic selective anticancer efficacy,inhibition of efflux pump ATPase,and antibiofilm formation of pathogens,these regimens may offer a promising therapeutic strategy to alleviate the severe side effects and drug resistance typically associated with chemotherapeutic agents.Further preclinical and clinical investigations are warranted.
基金supported by the Science and Technology Development Fund,Macao SAR,China(Grant Nos.:FDCT 0001/2020/AKP and 006/2023/SKL)Guangxi Science and Technology Major Program,China(Program No.:Guike AA22096022).
文摘Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.
基金financially supported by National Natural Science Foundation of China(Nos.32372610,U23A20201,32160661,32202359)National Key Research and Development Program of China(No.2022YFD1700300)the Central Government Guides Local Science and Technology Development Fund Projects(Nos.[Qiankehezhongyindi(2023)001]and[Qiankehezhongyindi[2024]007])。
文摘Structure-based virtual screening utilizing the approved drugs is an intriguing and laudable approach to excavate novel alternatives for different indications based on the vast amount of reported experimental data.Virus superfamily 1 helicase could resolve hydrogen bonds between base pairs and participate in nucleic acid replication and has emerged as a potential target for managing virus infection.Nonetheless,current drug exploitation targeting viral helicases is still in infancy.This work establishes an intelligent multi-computational screening programme to screen potential inhibitors targeting tobacco mosaic virus(TMV)helicase using Food and Drug Administration(FDA)-approved commercially available molecule library.The ranked top 6 hits were further validated by root mean square deviations/fluctuations(RMSD/F),molecular mechanics Poisson Boltzmann surface area(MM-PBSA),density functional theory(DFT)calculations,and bioactivity evaluation.Encouragingly,lumacaftor(ΔE_(total)=-29.0kcal/mol,K_(d)=0.22μmol/L,half maximal inhibitory concentration(IC_(50))=162.5μmol/L)displayed superior binding strength and enzyme inhibition against TMV helicase compared to ningnanmycin(K_(d)=9.35μmol/L,IC_(50)>200μmol/L).Therefore,lumacaftor may be able to inhibit TMV replication by binding to helicase and interfering with its biofunctionability.Besides,the lumacaftor-helicase binding mode changes from H-bonding/electrostatic interactions to hydrophobic interactions in trajectory analysis.Overall,current findings suggest this state-of-the-art stratagem is fruitful and has the potential to be engaged in rapid mining of other target inhibitors for disease treatment.
基金Supported by the National Natural Science Foundation of China,No.82273457the Natural Science Foundation of Guangdong Province,No.2023A1515012762Science and Technology Special Project of Guangdong Province,No.210715216902829.
文摘Colorectal cancer(CRC)ranks as the third most common cancer globally and the second leading cause of cancer-related deaths,representing a significant health burden.Despite advancements in traditional treatments such as surgery,chemotherapy,targeted therapy,and immunotherapy,these approaches still face challenges,including high costs,limited efficacy,and drug resistance.Drug repurposing has emerged as a promising strategy for CRC treatment,offering advantages with reduced development timelines,lower costs,and improved drug accessibility.This review explores drug repurposing strategies for CRC,supported by multidisciplinary technologies,and discusses the current challenges in the field.
基金supported by the National Natural Science Foundation of China(Grant No.:62101087)the China Postdoctoral Science Foundation(Grant No.:2021MD703942)+2 种基金the Chongqing Postdoctoral Research Project Special Funding,China(Grant No.:2021XM2016)the Science Foundation of Chongqing Municipal Commission of Education,China(Grant No.:KJQN202100642)the Chongqing Natural Science Foundation,China(Grant No.:cstc2021jcyj-msxmX0834).
文摘Drug repurposing offers a promising alternative to traditional drug development and significantly re-duces costs and timelines by identifying new therapeutic uses for existing drugs.However,the current approaches often rely on limited data sources and simplistic hypotheses,which restrict their ability to capture the multi-faceted nature of biological systems.This study introduces adaptive multi-view learning(AMVL),a novel methodology that integrates chemical-induced transcriptional profiles(CTPs),knowledge graph(KG)embeddings,and large language model(LLM)representations,to enhance drug repurposing predictions.AMVL incorporates an innovative similarity matrix expansion strategy and leverages multi-view learning(MVL),matrix factorization,and ensemble optimization techniques to integrate heterogeneous multi-source data.Comprehensive evaluations on benchmark datasets(Fdata-set,Cdataset,and Ydataset)and the large-scale iDrug dataset demonstrate that AMVL outperforms state-of-the-art(SOTA)methods,achieving superior accuracy in predicting drug-disease associations across multiple metrics.Literature-based validation further confirmed the model's predictive capabilities,with seven out of the top ten predictions corroborated by post-2011 evidence.To promote transparency and reproducibility,all data and codes used in this study were open-sourced,providing resources for pro-cessing CTPs,KG,and LLM-based similarity calculations,along with the complete AMVL algorithm and benchmarking procedures.By unifying diverse data modalities,AMVL offers a robust and scalable so-lution for accelerating drug discovery,fostering advancements in translational medicine and integrating multi-omics data.We aim to inspire further innovations in multi-source data integration and support the development of more precise and efficient strategies for advancing drug discovery and translational medicine.
基金Supported by the Instituto de Salud Carlos III,No.PI24/00784,No.PI24/00737,No.PI21/01181,No.PI21/00333 and No.INT22/00112Departamento de Universidad,Innovación y Transformación Digital Gobierno de Navarra,No.0011-1408-2024-000011,No.0011-1408-2022-000010.
文摘Gastric cancer(GC)is both the fifth most common cancer worldwide and the fifth in mortality.Owing to a lack of symptoms in the early stages and unspecific cli-nical presentation in the later stages,GC is usually diagnosed at advanced stages.This means that only approximately 60%of patients are eligible for curative treat-ment,and overall,GC patients have a 5-year survival rate of only 28.3%,under-scoring the importance of developing new treatment strategies.Drug repurposing involves identifying new therapeutic uses for approved drugs and is a promising strategy for cancer treatment because of its lower cost and faster development time.A variety of targetable pathways are involved in GC progression,including the mitogen-activated protein kinase,phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin,p53,Janus kinase 2/signal transducer and activator of transcription 3,hypoxia-inducible factor-1α,wingless-type mouse mammary tumor virus integration site family/beta-catenin(Wnt/β-catenin),nuclear factor kappa B,and Hippo pathways.Therefore,the repurposing of drugs targeting these pathways represents an interesting option in the search for new treatments for GC.In this review,we explore some relevant pathways involved in the development of GC and the possibilities of repurposing drugs that target them.
文摘The 2024 development of a precision-engineered retrotransposon system marked a significant milestone in mammalian genome-editing research.As appeared in the July 8 issue of Cell,this methodological breakthrough established a novel framework for site-specific gene delivery through repurposing ancient viral tools.
基金financially supported by the National Natural Science Foundation of China(Grant Nos.:32270690 and 32070671)the Postdoctor Research Fund of West China Hospital,Sichuan University,China(Grant No.:2024HXBH059)。
文摘Protozoan infections(e.g.,malaria,trypanosomiasis,and toxoplasmosis)pose a considerable global burden on public health and socioeconomic problems,leading to high rates of morbidity and mortality.Due to the limited arsenal of effective drugs for these diseases,which are associated with devastating side effects and escalating drug resistance,there is an urgent need for innovative antiprotozoal drugs.The emergence of drug repurposing offers a low-cost approach to discovering new therapies for protozoan diseases.In this review,we summarize recent advances in drug repurposing for various human protozoan diseases and explore cost-effective strategies to identify viable new treatments.We highlight the cross-applicability of repurposed drugs across diverse diseases and harness common chemical motifs to provide new insights into drug design,facilitating the discovery of new antiprotozoal drugs.Challenges and opportunities in the field are discussed,delineating novel directions for ongoing and future research.
基金supported by the Natural Science Foundation of China(Grant No.:21505009)the Natural Science Foundation of Chongqing,China(Grant No.:2023NSCQ-MSX0140)the Open Project of Central Nervous System Drug Key Laboratory of Sichuan Province,China(Grant No.:230012-01SZ).
文摘Computational approaches,encompassing both physics-based and machine learning(ML)methodologies,have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities.The human dopamine(DA)transporter(hDAT)is the primary therapeutic target of numerous psychiatric medications.However,traditional hDAT-targeting drugs,which interact with the primary binding site,encounter significant limitations,including addictive potential and stimulant effects.In this study,we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape(WHALES)descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs.Initially,WHALES descriptors facilitated a similarity search,employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates.Consequently,from a compound library of 4,921 marketed and clinically tested drugs,we identified 27 candidate atypical inhibitors.Subsequently,ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates,while induced-fit docking(IFD)was performed to estimate their binding affinities.Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities.Among these,three exhibited significant inhibitory potency,with half maximal inhibitory concentration(IC_(50))values of 0.753μM,0.542μM,and 1.210μM,respectively.Finally,molecular dynamics(MD)simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation.In conclusion,our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.
文摘Objective To improve the system of accelerated review and approval,and to speed up the development and marketing of repurposing drugs for rare diseases in China.Methods The relevant concepts of rare diseases and the definition of drug repurposing were introduced so as to sort out the advantages and disadvantages of the research and development of drug repurposing for rare diseases.Then,the incentive mechanisms of the research and development of drug repurposing for rare diseases in China and abroad were compared.Results and Conclusion Some suggestions on improving the incentive mechanism of repurposing drugs for rare diseases such as policy support for talents introduction,capital investment,and innovation capabilities are proposed.Besides,the government should further improve policies for the research and development of repurposing drugs for rare diseases,which can gradually narrow the gap between the research and innovation of drug repurposing in developed countries,thus benefiting the patients of rare diseases.
文摘BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast crisis chronic myeloid leukemia(BC-CML)is highly lethal.Advances in whole exome sequencing(WES)reveal pan-cancer mutations in BC-CML,supporting mutation-guided therapies beyond Breakpoint cluster region-Abelson.Artificial intelligence(AI)and machine learning(ML)enable genomic stratification and drug repurposing,addressing overlooked actionable mutations.AIM To stratify BC-CML into molecular subtypes using WES,ML,and AI for precision drug repurposing.METHODS Included 123 CML patients(111 CP-CML,5 AP-CML,7 BC-CML).WES identified pan-cancer mutations.Variants annotated via Ensembl Variant Effect Predictor and Catalogue of Somatic Mutations in Cancer(COSMIC).ML(principal component analysis,K-means)stratified BC-CML.COSMIC signatures and PanDrugs prioritized drugs.Analysis of variance/Kruskal-Wallis validated differences(P<0.05).RESULTS In this exploratory,hypothesis-generating study of BC-CML patients(n=7),we detected over 2500 somatic mutations.ML identified three BC-CML clusters:(1)Cluster 1[breast cancer susceptibility gene 2(BRCA2),TP53];(2)Cluster 2[isocitrate dehydrogenase(IDH)1/2,ten-eleven translocation 2];and(3)Cluster 3[Janus kinase(JAK)2,colony-stimulating factor 3 receptor],with distinct COSMIC signatures.Therapies:(1)Polyadenosinediphosphate-ribose polymerase inhibitors(olaparib);(2)IDH inhibitors(ivosidenib);and(3)JAK inhibitors(ruxolitinib).Mutational burden,signatures,and targets varied significantly across clusters,supporting precision stratification.CONCLUSION This WES-AI-ML framework provides mutation-guided therapies for BC-CML,enabling real-time stratification and Food and Drug Administration-approved drug repurposing.While this exploratory study is limited by its small sample size(n=7),it establishes a methodological framework for precision oncology stratification that warrants validation in larger,multi-center cohorts.
基金supported by the National Natural Science Foundation of China(82441036)Ganzhou Municipal Science and Technology Project(2022-RC1342)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2022B1515130004)Key-Area Research and Development Program of Guangdong Province(2019B020234003)Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer(2020B121201004)Open Project Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202210).
文摘Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC50 values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.
文摘Over the course of the past 70 years, the objectives of CA （cellular automata） research shifted from speculative and illustrative purposes without immediate goals outside of given implementations to the more utilitarian scientific and engineering objectives of simulating, controlling and predicting other phenomena. Looking back at our own 10-year history of CA related work, however, we recognize a generally inverse tendency from utilitarian objectives to finding more illustrative and speculative value. In this paper, we present a reflection on our own body of CA work, and we discuss the qualities of the various outcomes and insights we gained from a second-order cybernetic perspective. We argue that much of our own CA work may best be understood as creating machines for showing and for repurposing that allow their observers to gain new （second-order cybernetic） ways of seeing from interacting with them.
基金supported by the Spanish Ministry of Health(PI17/00828 and Ciberned)Galician Government(XUGA,ED431C 2018/10,ED431G/05)FEDER(Regional European Development Fund),all to AIRP.
文摘In the last decade,attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system,as insulin in the brain is implicated in neuronal survival,plasticity,oxidative stress and neuroinflammation.Diabetes mellitus and Parkinson’s disease are both aging-associated diseases that are turning into epidemics worldwide.Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson’s disease but can also determine the prognosis and progression of Parkinsonian symptoms.Today,there are no available curative or disease modifying treatments for Parkinson’s disease,but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson’s disease,both in diabetic and nondiabetic Parkinsonian patients.Furthermore,it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson’s disease.Here,we review the present evidence on the connection between Parkinson’s disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism,with a particular focus on glucagon-like peptide-1 receptor agonists.
基金funded by the National Natural Science Foundation of China(32270161,32100117,32100118)the Natural Science Foundation of Jiangsu Province of China(BK20210899,BK20210900,BK20210901)+1 种基金Research Grant of Jiangsu Commission of Health,China(ZD2021036)the Starting Grant for Talents of Xuzhou Medical University(D2021007,D2021008).
文摘Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.However,there are still unmet needs for treating chronic HEV infections.Herein,we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds.Upon screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities.Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection.Pyrazofurin selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains.Encouragingly,both drugs exhibited a sizeable therapeutic window against HEV.For instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients.Mechanistically,their anti-HEV mode of action depends on the blockage of pyrimidine synthesis.Notably,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral activity.In conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections.Based on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.
基金supported by grants from the National Natural Science Foundation of China(Grant No.81772830)。
文摘Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies,such as chemotherapy,radiotherapy,and molecular targeted therapy.Immunotherapy has emerged as a promising therapeutic modality but the efficacy has plateaued,which therefore provides limited benefits to patients with cancer.Identification of more effective approaches to improve patient outcomes and extend survival are urgently needed.Drug repurposing has emerged as an attractive strategy for drug development and has recently garnered considerable interest.This review comprehensively analyses the efficacy of various repurposed drugs,such as transforming growth factor-beta(TGF-β)inhibitors,metformin,receptor activator of nuclear factor-κB ligand(RANKL)inhibitors,granulocyte macrophage colony-stimulating factor(GM-CSF),thymosinα1(Tα1),aspirin,and bisphosphonate,in tumorigenesis with a specific focus on their impact on tumor immunology and immunotherapy.Additionally,we present a concise overview of the current preclinical and clinical studies investigating the potential therapeutic synergies achieved by combining these agents with immune checkpoint inhibitors.
