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drug repurposing screening and mechanism analysis based on human colorectal cancer organoids

Protein & Cell 2024年第4期15卷 285-304页

作者： Yunuo Mao Wei Wang Jingwei Yang Xin Zhou Yongqu Lu Junpeng Gao Xiao Wang Lu Wen Wei Fu Fuchou Tang School of Life Sciences Biomedical Pioneering Innovation CenterDepartment of General SurgeryThird HospitalPeking UniversityBeijing 100871China Beijing Advanced Innovation Center for Genomics(ICG) Ministry of Education Key Laboratory of Cell Proliferation and DifferentiationBeijing 100871China Peking-Tsinghua Center for Life Sciences Peking UniversityBeijing 100871China Peking University Third Hospital Cancer Center Beijing 100871China The Research Center of Stem Cell and Regenerative Medicine School of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Colorectal cancer(CRC)is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be ***,we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original *** efficiently identify repurposed drugs for CRC,we developed a robust organoid-based drug screening *** combining the repurposed drug library and computation-based drug prediction,335 drugs were tested and 34 drugs with anti-CRC effects were *** importantly,we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns:differentiation induction,growth inhibition,metabolism inhibition,immune response promotion,and cell cycle *** anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft(PDOX)system in *** found that fedratinib,trametinib,and bortezomib exhibited effective anticancer ***,the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were *** study offers an innovative approach for drug discovery,and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.

关键词： colorectal cancer organoids drug repurposing patient-derived organoids-based xenograft mechanism of action

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drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

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Virologica Sinica 2024年第1期39卷 123-133页

作者： Hongbo Guo Dan Liu Kuan Liu Yao Hou Chunyang Li Qiudi Li Xiaohui Ding Monique M.A.Verstegen Jikai Zhang Lingli Wang Yibo Ding Renxian Tang Xiucheng Pan Kuiyang Zheng Luc J.Wvan der Laan Qiuwei Pan Wenshi Wang Department of Pathogen Biology and Immunology Jiangsu Key Laboratory of Immunity and MetabolismJiangsu International Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhou221004China Department of Gastroenterology and Hepatology Erasmus MC-University Medical CenterRotterdamNL-3015 CNthe Netherlands Department of Surgery Erasmus MC Transplant InstituteUniversity Medical CenterRotterdam3015CENL-3015 CNthe Netherlands Department of Infectious Diseases The Affiliated Hospital of Xuzhou Medical UniversityXuzhou221002China

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 ***,there are still unmet needs for treating chronic HEV ***,we screened a best-in-class drug repurposing library consisting of 262 drugs/*** screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV *** calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 *** 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 ***,both drugs exhibited a sizeable therapeutic window against *** instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in ***,their anti-HEV mode of action depends on the blockage of pyrimidine ***,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral *** conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV *** 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.

关键词： Hepatitis Evirus(HEV) drug repurposing Vidofludimus calcium Pyrazofurin Pyrimidine biosynthesis

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Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent

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Acta Pharmaceutica Sinica B 2024年第2期14卷 729-750页

作者： Xin Chen Xianggang Mu Lele Ding Xi Wang Fei Mao Jinlian Wei Qian Liu Yixiang Xu Shuaishuai Ni Lijun Jia Jian Li State Key Laboratory of Bioreactor Engineering Shanghai Frontiers Science Center of Optogenetic Techniques for Cell MetabolismFrontiers Science Center for Materiobiology and Dynamic ChemistryShanghai Key Laboratory of New Drug DesignSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China Cancer Institute Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China College of Pharmacy Jinan UniversityGuangzhou 510632China

Chemotherapy-induced complications,particularly lethal cardiovascular diseases,pose significant challenges for cancer *** intertwined adverse effects,brought by cancer and its complication,further complicate anticancer therapy and lead to diminished clinical *** supplementation of cardioprotective agents falls short in addressing these *** bifunctional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events *** repurposing was naturally endowed with co-therapeutic potential of two indications,implying a unique chance in the development of bi-functional ***,we further proposed a novel“trilogy of drug repurposing”strategy that comprises function-based,targetfocused,and scaffold-driven repurposing approaches,aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional *** function-based repurposing,a cardioprotective agent,carvedilol(CAR),was identified as a potential neddylation inhibitor to suppress lung cancer *** target-focused SAR studies and scaffold-driven drug design,we synthesized 44 CAR derivatives to achieve a balance between anticancer and ***,optimal derivative 43 displayed promising bi-functional effects,especially in various self-established heart failure mice models with and without ***,the present study validated the practicability of the“trilogy of drug repurposing”strategy in the development of bi-functional cotherapy agents.

关键词： Anticancer Heartfailure Complication drug repurposing Bi-functional drug

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drug repurposing against coronavirus disease 2019(COVID-19):A review

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Journal of Pharmaceutical Analysis 2021年第6期11卷 683-690页

作者： Lianxiang Luo Qin Qiu Fangfang Huang Kaifeng Liu Yongqi Lan Xiaoling Li Yuge Huang Liao Cui Hui Luo Marine Biomedical Research Institute Guangdong Medical UniversityZhanjiang524023GuangdongChina Marine Medical Research Institute of Zhanjiang 524023GuangdongChina Graduate School Guangdong Medical University524023GuangdongChina The First Clinical College Guangdong Medical University524023GuangdongChina Animal Experiment Center Guangdong Medical University524023GuangdongChina Department of Pediatrics the Affiliated Hospital of Guangdong Medical University524023GuangdongChina Guangdong Key Laboratory for Research and Development of Natural drugs Guangdong Medical University524023GuangdongChina

Since December 2019,severe acute respiratory syndrome coronavirus 2 has been found to be the culprit in the coronavirus disease 2019(COVID-19),causing a global *** the existence of many vaccine programs,the number of confirmed cases and fatalities due to COVID-19 is still ***,a number of variants have been *** of the absence of approved anticoronavirus drugs,the treatment and management of COVID-19 has become a global *** these circumstances,drug repurposing is an effective method to identify candidate drugs with a shorter cycle of clinical ***,we summarize the current status of the application of drug repurposing in COVID-19,including drug repurposing based on virtual computer screening,network pharmacology,and bioactivity,which may be a beneficial COVID-19 treatment.

关键词： drug repurposing COVID-19 SARS-CoV-2 Virtual screening 3C-like protease

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drug repurposing for cancer treatment through global propagation with a greedy algorithm in a multilayer network

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Cancer Biology & Medicine 2022年第1期19卷 74-89页

作者： Xi Cheng Wensi Zhao Mengdi Zhu Bo Wang Xuege Wang Xiaoyun Yang Yuqi Huang Minjia Tan Jing Li Department of Bioinformatics and Biostatistics School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China The Chemical Proteomics Center and State Key Laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and HealthShanghai Institutes for Biological SciencesUniversity of Chinese Academy of SciencesChinese Academy of Sciences(CAS)Shanghai 200031China

Objective:drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug *** aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly ***:Here,by targeting 4,096 human diseases,including 384 cancers,we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in drug *** performed additional experimental validation for the dominant repurposed drugs in ***:The overall performance of the model was well supported by cross-validation and literature *** on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity *** of the distinctive antitumor effects of nifedipine(an antihypertensive agent)and nortriptyline(an antidepressant drug)in prostate cancer,we further explored their underlying mechanisms by using quantitative *** analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA ***,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft ***:Our predicted results,which have been released in a public database named The Predictive Database for drug repurposing(PAD),provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.

关键词： Database drug repurposing machine learning network random walk proteomics analysis

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drug repurposing for the Treatment of Mycobacterium abscessus Infections

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感染微生物与疾病(英文) 2023年第3期5卷 101-110页

作者： Emily J.Baker Antonia Molloy Jonathan A.G.Cox School of Life and Health Sciences Aston UniversityAston TriangleBirminghamUK.

With the ever-increasing burden of antimicrobial resistance,the demand to introduce countermeasures becomes increasingly *** urgency of this need is intensified by the void in antibiotic discovery,with the identification of novel compounds declining with *** increasing concern is Mycobacterium abscessus,which displays high levels of intrinsic resistance that lead to poor success rates,even after lengthy drug *** tackling these issues is now focused on the repurposing of preexisting drugs for antimycobacterial use,facilitating the discovery of antimicrobial compounds amidst a crisis where novel antibiotics are *** of this includes the use of combination treatments,whereby coadministration of synergistic compounds can reduce dose requirements and slow the progression of antimicrobial resistance in the long *** this review,we will introduce the current therapeutic options for *** and provide insight into why treatment is so *** will also compile the current updates within drug repurposing for this pathogen,including the use of unconventional agents such as antimalarial drugs,the repositioning of antitubercu-losis candidates and the repurposing of preexisting antibiotics,including the application of combination *** addition,the in vitro drug screening platforms used in their discovery will be appraised,with the view of highlighting potential future perspectives that may help increase physiological *** review provides a timely appraisal of the future of *** treatment.

关键词： drug repurposing Mycobacterium abscessus antimycobacterial drug discovery antimicrobials

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In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with drug repurposing Strategy

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Chinese Journal of Integrative Medicine 2020年第9期26卷 663-669页

作者： WEI Tian-zi WANG Hao WU Xue-qing LU Yi GUAN Sheng-hui DONG Feng-quan DONG Chen-le ZHU Gu-li BAO Yu-zhou ZHANG Jian WANG Guan-yu LI Hai-ying Department of Biology Southern University of Science and TechnologyShenzhen(518055)GuangdongChina School of Medicine Southern University of Science and TechnologyShenzhen(518055)GuangdongChina School of Biomedical Sciences Li Ka Shing Faculty of Medicinethe University of Hong KongHong Kong SARChina Department of Obstetrics and Gynecology Shenzhen University General HospitalShenzhen(518055)GuangdongChina Clinical Medical Academy Shenzhen UniversityShenzhen(518055)GuangdongChina Department of Cardiology Shenzhen University General HospitalShenzhen(518055)GuangdongChina Department of Obstetrics and Gynecology the First Affiliated Hospital of Wenzhou Medical UniversityWenzhou(325000)ZhejiangChina Guangdong Provincial Key Laboratory of Computational Science and Material Design Shenzhen(518055)GuangdongChina Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research Shenzhen(518055)GuangdongChina

Objective:To select potential molecules that can target viral spike proteins,which may potentially interrupt the interaction between the human angiotension-converting enzyme 2(ACE2)receptor and viral spike protein by virtual ***:The three-dimensional(3D)-coordinate file of the receptor-binding domain(RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and ***,approximately 15,000 molecular candidates were prepared,including US Food and drug Administration(FDA)-approved drngs from drugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology(TCMSP),for the docking ***,virtual screening was performed and the binding energy in Autodock Vina was ***,the top 20 molecules with high binding energy and their Chinese medicine(CM)herb sources were listed in this ***:It was found that digitoxin,a cardiac glycoside in drugBank and bisindigotin in TCMSP had the highest docking ***,two of the CM herbs containing the natural compounds that had relatively high binding scores,Forsyfh/ae frucft/s and/saf/d/s racWx,are components of Lianhua Qingwen(莲花清痕),a CM formula reportedly exerting activity against severe acute respiratory syndrome(SARS)-***,raltegravir,an HIV integrase inhibitor,was found to have a relatively high binding ***:A class of compounds,which are from FDA-approved drugs and CM natural compounds,that had high binding energy with RBD of the viral spike *** work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection,and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.

关键词： COVID-19 SARS-CoV-2 drug repurposing virtual screening Chinese medicine

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Paracelsus Paradox and drug repurposing for Cancer

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Journal of Oncology Research 2021年第2期3卷 46-54页

作者： Tomas Koltai Former Director of the Centro Gallego Hospital of Buenos Aires Buenos AiresArgentina

Dose is one of the parameters that any pharmacologist seriously considers when studying the effects of a *** the necessary dose to achieve a desired pharmacological effect is in a toxic or very toxic range for human use,the drug will probably fall out from further *** concentration that a drug can reach to its target organ or cell is a direct consequence of the administered dose and its pharmacodynamic *** researchers investigate at the cellular level or eventually with *** use different concentrations of the drug in order to determine its cellular ***,in many cases,these concentrations require doses that are in the toxic range or well beyond any clinically achievable ***,in these cases,research is in the realm of toxicology rather than *** paper will show some examples about this exercise in futility which is time and resource consuming but that pullulates the pages of many prestigious *** seasoned researchers seem to have forgotten the Paracelsus Paradox.

关键词： Dose bias drug repurposing Cancer Metformin Statins

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repurposing Loperamide as an Anti-Infection drug for the Treatment of Intracellular Bacterial Pathogens

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Engineering 2024年第8期39卷 180-193页

作者： Hongtao Liu Siqi Li Le Deng Zhenxu Shi Chenxiao Jiang Jingyan Shu Yuan Liu Xuming Deng Jianfeng Wang Zhimin Guo Jiazhang Qiu State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases&Key Laboratory of Zoonosis Research Ministry of EducationInstitute of ZoonosisCollege of Veterinary Medicine&Jilin UniversityChangchun 130062China Center for Pathogen Biology and Infectious Diseases The First Hospital of Jilin UniversityChangchun 130031China Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses Institute of Comparative MedicineCollege of Veterinary MedicineYangzhou UniversityYangzhou 225009China

Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within *** rapid development and dissemination of antimicrobial–resistant strains have exacerbated this *** the increasing knowledge of host–pathogen interactions,especially bacterial strategies for survival and proliferation within host cells,host-directed therapy(HDT)has attracted increased interest and has emerged as a promising antiinfection method for treating intracellular ***,we applied a cell-based screening approach to a US Food and drug Administration(FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium(***).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of *** intracellular *** treatment of infected cells markedly promoted the host autophagic response and lysosomal activity.A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B(GPNMB)induced by *** addition,LPD treatment effectively protected against *** infection in Galleria mellonella and mouse ***,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial ***,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.

关键词： Intracellular bacteria US Food and drug Administration(FDA)-approved drugs drug repurposing Loperamide Autophagy Glycoprotein nonmetastatic melanoma protein B

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repurposing of antitumor drug candidate Quisinostat lead to novel spirocyclic antimalarial agents

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Chinese Chemical Letters 2021年第5期32卷 1660-1664页

作者： Ruoxi Li Dazheng Ling Tongke Tang Zhenghui Huang Manjiong Wang Fei Mao Jin Zhu Lubin Jiang Jian Li Xiaokang Li State Key Laboratory of Bioreactor Engineering Shanghai Key Laboratory of New Drug DesignSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China Key Laboratory of Molecular Virology and Immunology Institut Pasteur of ShanghaiUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China College of Pharmacy and Chemistry Dali UniversityDali 671000China Frontiers Science Center for Materiobiology and Dynamic Chemistry East China University of Science and TechnologyShanghai 200237China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China

Antimalarial chemotherapies endowed with effectiveness against drug-resistant parasites and good safety are urgently required in *** previous research revealed that clinical phaseⅡantitumor drug Quisinostat was a promising antimalarial prototype by inhibiting the activity of Plasmodium falciparum(***)histone deacetylase(PfHDAC).Herein,30 novel spirocyclic linker derivatives were designed and synthesized based on Quisinostat as lead compound,and then their antimalarial activities and cytotoxicity were systematically *** them,compounds 8 and 27 could effectively eliminate wild-type and multi-drug resistant *** parasites,and display weakened cytotoxicity and good metabolic *** blot assay demonstrated that they could inhibit PfHDAC activity like *** addition,both 8 and 27 showed certain antimalarial efficacy in rodent malaria model,and the animal toxicity of 8 was significantly improved compared with ***,8 and 27 were structurally novel PfHDAC inhibitors and provided prospective prototype for further antimalarial drug research.

关键词： Malaria PfHDAC inhibitor drug repurposing Epigenetic modulator Erythrocytic therapy

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