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Novel Pt(IV) complex OAP2 induces STING activation and pyroptosis via mitochondrial membrane remodeling for synergistic chemo-immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1742-1758页

作者： Renming Fan Ruizhuo Lin Shuo Zhang Aohua Deng Yongrui Hai Junyan Zhuang Yang Liu Maosheng Cheng Gaofei Wei Institute of Medical Research Northwestern Polytechnical UniversityXi'an 710072China Research&Development Institute of Northwestern Polytechnical University in Shenzhen Shenzhen 518057China key laboratory of Structure-Based drug design and discovery Ministry of EducationSchool of Pharmaceutical EngineeringShenyang Pharmaceutical UniversityShenyang 110016China

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.

关键词： Anti-tumor drug Prodrug Platinum Chemo-immunotherapy Mitochondrial membrane modeling STING Pyroptosis mtDNA

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SRY-Box transcription factor 9 triggers YAP nuclear entry via direct interaction in tumors

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2285-2297页

作者： Hui Qian Chen-Hong Ding Fang Liu Shi-Jie Chen Chen-Kai Huang Meng-Chao Xiao Xia-Lu Hong Ming-Chen Wang Fang-Zhi Yan Kai Ding Ya-Lu Cui Bai-Nan Zheng Jin Ding Cheng Luo Xin Zhang Wei-Fen Xie Department of Gastroenterology Changzheng HospitalNaval Medical UniversityShanghaiChina Department of Gastroenterology Shanghai East HospitalSchool of MedicineTongji UniversityShanghaiChina drug discovery and design Center CAS Key Laboratory of Receptor ResearchState Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina Department of Gastroenterology First Affiliated Hospital of Nanchang UniversityNanchangChina Clinical Cancer Institute Center for Translational MedicineNaval Medical UniversityShanghaiChina

The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor ***,the precise molecular mechanisms governing the nuclear import of YAP are not fully *** this study,we have uncovered a crucial role of SOX9 in the activation of ***9 promotes the nuclear translocation of YAP by direct ***,we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of ***,we have discovered a novel asymmetrical dimethylation of YAP at Arg-124(YAP-R124me2a)catalyzed by ***-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple ***,we disrupted the interaction between SOX9 and YAP using a competitive peptide,S-A1,which mimics anα-helix of SOX9 containing Asp-125.S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor *** study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.

关键词： interaction interaction precise

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Asymmetric Synthesis of Dihydrospirotryprostatin B via a Silica Gel-Mediated Cyclization of Tryptamine-Ynamide

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Chinese Journal of Chemistry 2024年第12期42卷 1355-1359页

作者： Changhong Han Lu Yang Kaizong Yao Sen Zhang Jiayue Fu Hanyang Sun Hongsheng Xu Bin Lin Maosheng Cheng Yongxiang Liu key laboratory of Structure:Based drug design and discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyangLiaoning 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyangLiaoning 110016China Institute of drug Research in Medicine Capital of China BenxiLiaoning 117000China Zhejiang Shapuaisi Pharmaceutical Co. LtdPinghuZhejiang 314299China

Comprehensive Summary An asymmetric synthesis of dihydrospirotryprostatin B was achieved in 15 steps(8 purifications)from *** main feature of our synthetic strategy is the efficient construction of spirocyclic oxindole intermediate containing a chiral quaternary carbon center,involving the silica gel-mediated cyclization of tryptamine-ynamide and oxidation under neat conditions.

关键词： Asymmetric synthesis Alkaloids Dihydrospirotryprostatin B Tryptamine-ynamide Cross-coupling Silica gel-mediated cyclization Oxidation

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“Three-in-one” strategy of trifluoromethyl regulated blood-brain barrier permeable fluorescent probe for peroxynitrite and antiepileptic evaluation of edaravone

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Chinese Chemical Letters 2024年第10期35卷 360-363页

作者： Lei Shen Hongmei Liu Ming Jin Jinchao Zhang Caixia Yin Shuxiang Wang Yutao Yang key laboratory of Medicinal Chemistry and molecular Diagnosis of the Ministry of Education Chemical Biology Key Laboratory of Hebei ProvinceState Key Laboratory of New Pharmaceutical Preparations and ExcipientsCollege of Chemistry and Materials ScienceHebei UniversityBaoding 071002China key laboratory of Chemical Biology and molecular Engineering of Ministry of Education Institute of Molecular ScienceShanxi UniversityTaiyuan 030006China

Epilepsy,as a chronic neurological disease of the brain,is closely related to oxidative stress,and the peroxynitrite(ONOO-)significantly rise up in this ***,ONOO-is considered as a potential biomarker for early prediction of ***,some potential diagnostic reagents for epilepsy are hindered by the blood-brain barrier(BBB).Meanwhile,“drug repurposing”is attracting a growing ***(EDA),as a first-line drug in the clinical treatment of cerebral ischemia,plays antioxidant roles in scavenging free radicals,promising potential antiepileptic ***,it is imperative to develop fluorescent probes for monitoring ONOO-fluctuations in the epileptic ***,we proposed a novel fluorescent probe with the thiocarbonate as the promising recognition unit for ONOO-and dicyanoisophorone derivative as the ***,by the“three-in-one”strategy,the introduction of trifluoromethyl into DCI-ONOO-3 can extend the emission wavelength of the fluorophore,shorten the response and increase ***,DCI-ONOO-3 was used for monitoring ONOO-fluxes in brain of epileptic mice and evaluating the antiepileptic efficacy of *** opens up a new way for the design of BBB permeable fluorescent probes,and provides a convincing new method for the diagnosis and treatment of epilepsy.

关键词： Fluorescent probe Blood-brain barrier Peroxynitrite Epilepsy drug repurposing

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Evolving roles of glycosylation in the tug-of-war between virus and host

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National Science Review 2024年第5期11卷 100-104页

作者： Xiaofeng Zhai Yanqiu Yuan Wan-Ting He Ying Wu Yi Shi Shuo Su Quansheng Du Yang Mao Academy for Advanced Interdisciplinary Studies Engineering Laboratory of Animal Immunity of Jiangsu Province College of Veterinary MedicineNanjing Agricultural University State key laboratory of Anti-Infective drug discovery and Development School of Pharmaceutical SciencesSun Yat-sen University School of Pharmacy China Pharmaceutical University Guangdong Provincial key laboratory of drug Non-Clinical Evaluation and Research School of Pharmaceutical Sciences Sun Yat-sen University CAS key laboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Department of Interdisciplinary Sciences National Natural Science Foundation of China

Covering the surface of both host cells and enveloped viruses, glycans are inevitable biomolecules for investigating virus–host interactions. However, due to the intricate role of glycans in the viral–host relationship, few glycanrelated molecular mechanisms have been harnessed for antiviral therapies. The intricacy arises from multiple factors.

关键词： VACCINE BINDING PROTEIN

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discovery of Novel Anthranilic Diamide Derivatives Bearing Sulfoximine Group as Potent Insecticide Candidates

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Chemical Research in Chinese Universities 2024年第1期40卷 96-108页

作者： ZHANG Hongyuan PENG Jinmin ZHONG Yuanhan CHEN Yue WANG Qing Haditullah HADIATULLAH XIE Weibin XIONG Lixia YUCHI Zhiguang LIU Jingbo LI Yuxin State key laboratory of Elemento-Organic Chemistry College of ChemistryNankai UniversityTianjin300071P.R.China Nankai University&Cangzhou Bohai New Area Institute of Green Chemical Engineering Changzhou062550P.R.China College of Horticulture and Landscape Architecture Tianjin Agricultural UniversityTianjin300392P.R.China tianjin key laboratory for Modern drug Delivery and High-efficiency Collaborative Innovation Center of Chemical Science and EngineeringSchool of Pharmaceutical Science and TechnologyTianjin UniversityTianjin300072P.R.China

The fall armyworm,Spodoptera frugiperda(***),represents the most resistant insect species and poses serious threat to grain ***(CHL),which targets the ryanodine receptors(RyRs)in insects,has demonstrated the efficacy in controlling ***,this has led to emerging resistance in several *** counter this resistance,a viable approach involves the development of novel compounds that bind against RyRs via distinct binding sites or *** this study,a series of 22 novel anthranilic diamide derivatives was designed and synthesized,and their insecticidal activities were *** of these derivatives showed moderate to good insecticidal activity against *** and Mythimna ***-lapse fluorescence measurements of endoplasmic reticulum luminal calcium revealed that most derivatives elicited cellular responses similar as CHL when assessed on HEK293 cells expressing *** ryanodine receptors(SfRyRs).The mode of action of compound 13a was studied and verified on the isolated neurons by calcium imaging ***,molecular docking analysis was employed to predict the binding mechanism of compound 13a against ***,these novel diamide derivatives hold promise as a valuable resource for guiding the future design of insecticidal compounds targeting RyRs.

关键词： Anthranilic diamide derivative Sulfoximine Spodoptera frugiperda Mode of action molecular docking

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β-Carboline alkaloids from the roots of Peganum harmala L.

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Chinese Journal of Natural Medicines 2024年第2期22卷 171-177页

作者： LI Shengge ZHANG Qin WANG Yuetong LIN Bin LI Dahong HUA Huiming HU Xu Henan key laboratory of Zhang Zhongjing Formulate and Herbs for Immunoregulation Zhang Zhongjing Traditional School of Chinese MedicineNanyang Institute of TechnologyNanyang 473004China key laboratory of Structure-Based drug design&discovery Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China School of Pharmaceutical Engineering Shenyang Pharmaceutical UniversityShenyang 110016China

This study reports the isolation of four newβ-carboline alkaloids(1−4)and six previously identified alkaloids(5−10)from the roots of Peganum harmala *** these compounds,1 and 2 were characterized as rareβ-carboline-quinazoline dimers exhibiting axial *** 3 possessed a unique 6/5/6/7 tetracyclic ring system with an azepine ring,and compound 4 was a novel annomontineβ-*** structures of these compounds were elucidated by spectroscopic data and quantum mechanical *** biosynthetic pathways of 1−3 were ***,the cytotoxicity of some isolates against four cancer cell lines(HL-60,A549,MDA-MB-231,and DU145)was ***,compound 4 exhibited significant cytotoxicity against HL-60,A549,and DU145 cells with IC_(50) values of 12.39,12.80,and 30.65μmol·L^(−1),***,compound 2 demonstrated selective cytotoxicity against HL-60 cells with an IC_(50) value of 17.32μmol·L^(−1).

关键词： β-Carboline alkaloids Peganum harmala Structure elucidation Cytotoxic activity

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A proteomic landscape of pharmacologic perturbations for functional relevance

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Journal of Pharmaceutical Analysis 2024年第1期14卷 128-139页

作者： Zhiwei Liu Shangwen Jiang Bingbing Hao Shuyu Xie Yingluo Liu Yuqi Huang Heng Xu Cheng Luo Min Huang Minjia Tan Jun-Yu Xu State key laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing210023China Zhongshan Institute for drug discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdong528400China State key laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing210023China

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.

关键词： Proteomics drug Perturbation drug target drug combination

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In silico off-target profiling for enhanced drug safety assessment

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2927-2941页

作者： Jin Liu Yike Gui Jingxin Rao Jingjing Sun Gang Wang Qun Ren Ning Qu Buying Niu Zhiyi Chene Xia Sheng Yitian Wang Mingyue Zheng Xutong Li College of Pharmaceutical Sciences Zhejiang UniversityHangzhou 310058China drug discovery and design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Nanjing University of Chinese Medicine Nanjing 210023China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyHangzhou 330106China

Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent ***,the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is *** off-target interactions,along with the adverse drug reactions they induce,are significant factors affecting drug *** assess the liability of candidate drugs,we developed an artificial intelligence model for the precise prediction of compound off-target interactions,leveraging multi-task graph neural *** outcomes of off-target predictions can serve as representations for compounds,enabling the differentiation of drugs under various ATC codes and the classification of compound ***,the predicted off-target profiles are employed in adverse drug reaction(ADR)enrichment analysis,facilitating the inference of potential ADRs for a *** the withdrawn drug Pergolide as an example,we elucidate the mechanisms underlying ADRs at the target level,contributing to the exploration of the potential clinical relevance of newly predicted off-target ***,our work facilitates the early assessment of compound safety/toxicity based on off-target identification,deduces potential ADRs of drugs,and ultimately promotes the secure development of drugs.

关键词： drug safety Off-target prediction Adverse drug reactions Toxicity molecular representation Artificial intelligence

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Directly targeting BAX for drug discovery:Therapeutic opportunities and challenges

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2378-2401页

作者： Zhenwei Zhang Linghui Hou Dan Liu Shenglin Luan Min Huang Linxiang Zhao key laboratory of Structure-Based drugs design&discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China China Resources Sanjiu Medical&Pharmaceutical Co. Ltd.Shenzhen 518000China

For over two decades,the development of B-cell lymphoma-2(Bcl-2)family therapeutics has primarily focused on anti-apoptotic proteins,resulting in the first-in-class drugs called BH3 mimetics,especially for Bcl-2 inhibitor *** pro-apoptotic protein Bcl-2-associated X protein(BAX)plays a crucial role as the executioner protein of the mitochondrial regulated cell death,contributing to organismal development,tissue homeostasis,and *** dysregulation of BAX is closely associated with the onset and progression of diseases characterized by pathologic cell survival or death,such as cancer,neurodegeneration,and heart *** addition to conducting thorough investigations into the physiological modulation of BAX,research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX,as well as diverse all-molecule BAX *** review presents recent advancements in elucidating the physiological and pharmacological modulation of BAX and in identifying potentially druggable binding sites on ***,it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or conformations of BAX,offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX.

关键词： Apoptosis Pro-apoptotic protein BAX Dynamic conformational activation Small-molecule apoptosis modulators

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