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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 addressed.Here,we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors.To efficiently identify repurposed drugs for CRC,we developed a robust organoid-based drug screening system.By combining the repurposed drug library and computation-based drug prediction,335 drugs were tested and 34 drugs with anti-CRC effects were identified.More 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 inhibition.The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft(PDOX)system in vivo.We found that fedratinib,trametinib,and bortezomib exhibited effective anticancer effects.Furthermore,the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated.Our 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 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.

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 survivors.The intertwined adverse effects,brought by cancer and its complication,further complicate anticancer therapy and lead to diminished clinical outcomes.Simple supplementation of cardioprotective agents falls short in addressing these challenges.Developing bifunctional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously.drug repurposing was naturally endowed with co-therapeutic potential of two indications,implying a unique chance in the development of bi-functional agents.Herein,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 agent.Through function-based repurposing,a cardioprotective agent,carvedilol(CAR),was identified as a potential neddylation inhibitor to suppress lung cancer growth.Employing target-focused SAR studies and scaffold-driven drug design,we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection.Remarkably,optimal derivative 43 displayed promising bi-functional effects,especially in various self-established heart failure mice models with and without tumor-bearing.Collectively,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 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 development.The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly cancers.Methods: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 Bank.We performed additional experimental validation for the dominant repurposed drugs in cancer.Results:The overall performance of the model was well supported by cross-validation and literature mining.Focusing on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments.Because 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 proteomics.Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA transport.Moreover,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model.Conclusions: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 critical.The urgency of this need is intensified by the void in antibiotic discovery,with the identification of novel compounds declining with time.Of increasing concern is Mycobacterium abscessus,which displays high levels of intrinsic resistance that lead to poor success rates,even after lengthy drug regimens.Research 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 sparse.Part 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 term.In this review,we will introduce the current therapeutic options for M.abscessus and provide insight into why treatment is so burdensome.We 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 regimens.In 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 relevance.This review provides a timely appraisal of the future of M.abscessus treatment.

关键词： drug repurposing Mycobacterium abscessus antimycobacterial drug discovery antimicrobials

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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 pandemic.Despite the existence of many vaccine programs,the number of confirmed cases and fatalities due to COVID-19 is still increasing.Furthermore,a number of variants have been reported.Because of the absence of approved anticoronavirus drugs,the treatment and management of COVID-19 has become a global challenge.Under these circumstances,drug repurposing is an effective method to identify candidate drugs with a shorter cycle of clinical trials.Here,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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The interplay of drug therapeutics and immune responses to SARS-CoV-2

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Cellular & Molecular Immunology 2024年第2期21卷 197-200页

作者： Valeria Fumagalli Matteo Iannacone Division of Immunology Transplantationand Infectious DiseasesIRCCS San Raffaele Scientific InstituteMilanItaly Vita-Salute San Raffaele University MilanItaly Experimental Imaging Centre IRCCS San Raffaele Scientific InstituteMilanItaly

The SARS-CoV-2 pandemic has necessitated rapid therapeutic and preventative responses.While vaccines form the frontline of defense,antiviral treatments such as nirmatrelvir have emerged as vital adjunctive measures,particularly for those unable or unwilling to be vaccinated.This review delves into the potential influence of nirmatrelvir on enduring immunity.In parallel,the potential of drug repurposing is explored,with bisphosphonates being examined for their possible effects against COVID-19 due to their immunomodulatory properties.The importance of rigorous clinical trials and careful interpretation of preliminary data is emphasized.

关键词： SARS-CoV-2 Nirmatrelvir Bisphosphonates Adaptive immunity drug repurposing

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repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1711-1725页

作者： Yingting Wu Jiaqi Xin Xinyu Li Ting Yang Yi Liu Yongsheng Zhao Wen Xie Mengxi Jiang Department of Pharmacology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Department of Traditional Chinese Medicine Capital Medical UniversityBeijing 100069China Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPA 15261USA Advanced Innovation Center for Human Brain Protection Capital Medical UniversityBeijing 100069China

drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal ulcers.We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in mice.Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism.Mechanistically,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent manner.Our results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor signaling.In summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.

关键词： Lansoprazole Proton pump inhibitors Adipose thermogenesis Energy expenditure Metabolic syndrome PHOSPHO1 inhibitor Cannabinoid receptor signaling drug repurposing

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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 screening.Methods:The three-dimensional(3D)-coordinate file of the receptor-binding domain(RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared.Secondly,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 process.Then,virtual screening was performed and the binding energy in Autodock Vina was calculated.Finally,the top 20 molecules with high binding energy and their Chinese medicine(CM)herb sources were listed in this paper.Results:It was found that digitoxin,a cardiac glycoside in drugBank and bisindigotin in TCMSP had the highest docking scores.Interestingly,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)-Cov-2.Moreover,raltegravir,an HIV integrase inhibitor,was found to have a relatively high binding score.Conclusions: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 protein.Our 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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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 clinical.Our previous research revealed that clinical phaseⅡantitumor drug Quisinostat was a promising antimalarial prototype by inhibiting the activity of Plasmodium falciparum(P.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 evaluated.Among them,compounds 8 and 27 could effectively eliminate wild-type and multi-drug resistant P.falciparum parasites,and display weakened cytotoxicity and good metabolic stability.Western blot assay demonstrated that they could inhibit PfHDAC activity like Quisinostat.In addition,both 8 and 27 showed certain antimalarial efficacy in rodent malaria model,and the animal toxicity of 8 was significantly improved compared with Quisinostat.Overall,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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