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DNA G-Quadruplexes as Targets for Natural Product Drug Discovery

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Engineering 2024年第7期38卷 39-51页

作者： Kai-Bo Wang Yingying Wang Jonathan Dickerhoff Danzhou Yang borch department of medicinal chemistry and molecular pharmacology College of PharmacyPurdue UniversityWest LafayetteIN 47907USA Purdue Center for Cancer Research Purdue UniversityWest LafayetteIN 47907USA department of chemistry Purdue UniversityWest LafayetteIN 47907USA Purdue Institute for Drug Discovery Purdue UniversityWest LafayetteIN 47907USA Jiangsu Key Laboratory of Bioactive Natural Product Research&State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

DNA guanine(G)-quadruplexes(G4s)are unique secondary structures formed by two or more stacked Gtetrads in G-rich DNA *** structures have been found to play a crucial role in highly transcribed genes,especially in cancer-related oncogenes,making them attractive targets for cancer ***,targeting oncogene promoter G4 structures has emerged as a promising strategy to address the challenge of undruggable and drug-resistant proteins,such as MYC,BCL2,KRAS,and *** products have long been an important source of drug discovery,particularly in the fields of cancer and infectious *** progress has recently been made in the discovery of naturally occurring DNA G4-targeting *** DNA G4s,such as MYC-G4,BCL2-G4,KRAS-G4,PDGFR-b-G4,VEGF-G4,and telomeric-G4,have been identified as potential targets of natural products,including berberine,telomestatin,quindoline,sanguinarine,isaindigotone,and many ***,we summarize and evaluate recent advancements in natural and nature-derived DNA G4 binders,focusing on understanding the structural recognition of DNA G4s by small molecules derived from *** also discuss the challenges and opportunities associated with developing drugs that target DNA G4s.

关键词： G-quadruplex Natural products Alkaloids Cancer Promoter

Site-specific incorporation of reduction-controlled guest amino acids into proteins for cucurbituril recognition

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Chinese Chemical Letters 2024年第5期35卷 193-196页

作者： Zhen Dai Linzhi Tan Yeyu Su Kerui Zhao Yushun Tian Yu Liu Tao Liu College of chemistry State Key Laboratory of Elemento-Organic ChemistryNankai UniversityTianjin 300071China State Key Laboratory of Natural and Biomimetic Drugs Department of Molecular and Cellular PharmacologySchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China

Protein recognition using host-guest recognition approach is of great interest but has been limited mainly to the protein N-terminal ***,we site-specific incorporated two novel non-canonical amino acids containing supramolecular guest motifs into protein via an expanded genetic *** Staudinger reduction reactions,the encoded unnatural residues on protein becoming activated and can be specifically recognized by cucurbit[7]uril(CB[7])and cucurbit[8]uril(CB[8]).We demonstrated that enzyme containing guest amino acid incorporated near the active site can be reversibly regulated by CB[7]recognition,and CB[8]recognition induces protein *** amino acids will make useful addition to the supramolecular toolbox for protein targeting using molecular recognition approaches.

关键词： Protein recognition Host-guest recognition Non-canonical amino acids Staudinger reduction Expanded genetic code

Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael S.Wolfe Computational Medicine Program and department of pharmacology University of North Carolina–Chapel HillChapel HillNCUSA department of medicinal chemistry University of KansasLawrenceKSUSA

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

Parallelogram 3d-4f-5d heterometallic clusters based on trilacunary tungstoantimonates with excellent proton conductivity

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Chinese Chemical Letters 2024年第3期35卷 528-531页

作者： Haiying Wang Han Xu Chaolong Chen Yingjie Zhu Yikang Zhang Dongdi Zhang Jingyang Niu Henan Key Laboratory of Polyoxometalate chemistry College of Chemistry and Molecular SciencesHenan UniversityKaifeng 475004China School of Pharmaceutical Science&Yunnan Key Laboratory of pharmacology for Natural Products Kunming Medical UniversityKunming 650500China Collaborative Innovation Center of chemistry for Energy Materials State Key Laboratory of Physical Chemistry of Solid Surface and Department of ChemistryCollege of Chemistry and Chemical EngineeringXiamen UniversityXiamen 361005China

Two 3d-4f-5d heterometallic cluster-containing polyoxometalates,formulated as Na_(22){(SbW_(9)O_(33))_(4)[La_(3)W_(6)MO_(18)(H_(2)O)_(8)(CH_(3)COO)_(4)]_(2)}·nH_(2)O(abbreviated as La_(6)M_(2),M=Co/Mn)were synthesized and structurally ***-crystal X-ray diffraction analyses reveal that the polyanions of La_(6)Co_(2)and La_(6)Mn_(2)consist of the uncommon 3d-4f-5d clusters{La_(6)W_(12)Co_(2)}and{La_(6)W_(12)Mn_(2)},which are encapsulated by four trilacunary Keggin tungstoantimonates to form the parallelogram-shaped title ***,the polyanions can be extended into a two-dimensional(2D)frame by the linkage of peripheral Na+*** inner space of the 2D layer was filled with water molecules and thus an H-bonded network was formed,which is expected to exhibit a fascinating proton *** study of water-assisted proton conduction demonstrated that La_(6)Co_(2)and La_(6)Mn_(2)were temperature-and humiditydependent proton conductors,respectively,and the proton conductivities could reach 1.3×10^(-2)and 2.3×10^(-2)S/cm at 65℃and 90%RH conditions.

关键词： Polyoxometalate Parallelogram Heterometallic 3d-4f-5d cluster Proton conductivity

medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

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Acta Pharmaceutica Sinica B 2024年第1期14卷 87-109页

作者： Letian Song Shenghua Gao Bing Ye Mianling Yang Yusen Cheng Dongwei Kang Fan Yi Jin-Peng Sun Luis Menéndez-Arias Johan Neyts Xinyong Liu Peng Zhan department of medicinal chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Shenzhen Research Institute of Shandong University Shenzhen 518057China The Key Laboratory of Infection and Immunity of Shandong Province Department of PharmacologySchool of Basic Medical SciencesShandong UniversityJinan 250012China Key Laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Centro de Biologı´a molecular“Severo Ochoa”(Consejo Superior de Investigaciones Cientı´ficas&Autonomous University of Madrid) Madrid 28049Spain KU Leuven Department of Microbiology and ImmunologyRega Institute for Medical ResearchLaboratory of Virology and ChemotherapyLeuven 3000Belgium

The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life *** covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic *** antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable *** non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available *** viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.

关键词： COVID-19 SARS-CoV-2 Main protease Non-covalent inhibitors medicinal chemistry strategies

Method for the extraction of circulating nucleic acids based on MOF reveals cell-free RNA signatures in liver cancer

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National Science Review 2024年第1期11卷 94-106页

作者： Yuqing Sun Haixin Yu Shaoqing Han Ruoxi Ran Ying Yang Yongling Tang Yuhao Wang Wenhao Zhang Heng Tang Boqiao Fu Boshi Fu Xiaocheng Weng Song-Mei Liu Hexiang Deng Shuang Peng Xiang Zhou College of chemistry and molecular Sciences Key Laboratory of Biomedical Polymers-Ministry of Education Wuhan University department of Digestive Surgical Oncology Union Hospital Tongji Medical College Huazhong University of Science and Technology Cancer Center Union HospitalTongji Medical CollegeHuazhong University of Science and Technology department of Clinical Laboratory Center for Gene Diagnosis and Program of Clinical Laboratory Zhongnan Hospital of Wuhan University College of chemistry and Materials Science Hubei Engineering University department of pharmacology School of Pharmacy China Medical University Taikang Center for Life and Medical Sciences Wuhan University department of Hematology Zhongnan Hospital of Wuhan University

Cell-free RNA(cf RNA) allows assessment of health, status, and phenotype of a variety of human organs and is a potential biomarker to non-invasively diagnose numerous diseases. Nevertheless, there is a lack of highly efficient and bias-free cf RNA isolation technologies due to the low abundance and instability of cf ***, we developed a reproducible and high-efficiency isolation technology for different types of cell-free nucleic acids(containing cf RNA and viral RNA) in serum/plasma based on the inclusion of nucleic acids by metal-organic framework(MOF) materials, which greatly improved the isolation efficiency and was able to preserve RNA integrity compared with the most widely used research kit method. Importantly, the quality of cf RNA extracted by the MOF method is about 10-fold that of the kit method, and the MOF method isolates more than three times as many different RNA types as the kit method. The whole transcriptome mapping characteristics of cf RNA in serum from patients with liver cancer was described and a cf RNA signature with six cf RNAs was identified to diagnose liver cancer with high diagnostic efficiency(area under curve = 0.905 in the independent validation cohort) using this MOF method. Thus, this new MOF isolation technique will advance the field of liquid biopsy, with the potential to diagnose liver cancer.

关键词： MOF circulating cell-free RNA biomarker liver cancer diagnosis

Uncovering Chemical Interactions between Danshen and Danggui Using Liquid Chromatography–Mass Spectrometry and Network pharmacology-Based Research on Stroke

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World Journal of Traditional Chinese Medicine 2024年第2期10卷 230-243页

作者： Han-Qing Pang Jia-Xiu Guo Xiao-Yu Shang Jian Wang Hui Liu Jing Tian Lu Zhang Jian-Bin Wang Wei Shi Bing-Chun Yan Liang Liu department of Pharmacy School of MedicineInstitute of Translational MedicineYangzhou UniversityYangzhouChina School of Medicine Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile DiseasesYangzhou UniversityYangzhouChina School of chemistry and Pharmaceutical Sciences State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources(Guangxi Normal University)GuilingChina Yangzhou Food and Drug Inspection and Testing Center YangzhouChina

Objective: The objective of this study was to decipher chemical interactions between Danshen and Danggui using liquid chromatography–mass spectrometry(LC-MS) and explore the mechanisms of Danshen–Danggui against stroke using network pharmacology and molecular docking. Materials and Methods: First, the chemical compounds of Danshen–Danggui were profiled using ultra-high-performance liquid chromatography(HPLC)-quadrupole time-of-flight MS. Accurately characterized compounds in various proportions of Danshen–Danggui were quantified using HPLC combined with triple quadrupole electrospray tandem MS. Network pharmacology was used to uncover the essential mechanisms of action of Danshen–Danggui against stroke. Discovery Studio Software was used for the molecular docking verification of key active chemicals and stroke-related targets. Results: A total of 53 compounds were characterized, and 22 accurately identified constituents(10 phenolic acids, 8 phthalides, and 4 tanshinones) were quantified in 15 proportions of Danshen–Danggui. The quantification results showed that Danggui significantly increased the dissolution of most phenolic acids(compounds from Danshen), whereas Danshen promoted the dissolution of most phthalides(compounds from Danggui). Overall, the combination of Danshen and Danggui at a 1:1 ratio resulted in the maximum total dissolution rate. Further network pharmacology and molecular docking results indicated that Danshen–Danggui exerted anti-stroke effects mainly by regulating inflammation-related(tumor necrosis factor, hypoxia-inducible factor, and toll-like receptor) signaling pathways, which ranked among the top three pathways based on Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. Conclusion: The chemical compounds in Danshen–Danggui could interact with each other to increase the dissolution of the most active compounds, which could provide a solid basis for uncovering the compatibility mechanisms of Danshen–Danggui and Danshen–Danggu

关键词： Chemical interactions Danggui Danshen liquid chromatography–mass spectrometry network pharmacology

The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer

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Research 2024年第1期2023卷 119-130页

作者： Ding Ding Haitao Zhao Dali Wei Qinglai Yang Cai Yang Ruowen Wang Yumei Chen Lianghua Li Shuxian An Qian Xia Gang Huang Jianjun Liu Zeyu Xiao Weihong Tan Institute of molecular Medicine(IMM) Renji HospitalState Key Laboratory of Oncogenes and Related GenesShanghai Jiao Tong University School of Medicineand College of Chemistry and Chemical EngineeringShanghai Jiao Tong UniversityShanghai 200240China department of Nuclear Medicine Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China Center for molecular Imaging Probes Cancer Research InstituteUniversity of South ChinaHengyangHunan 421001China The Key Laboratory of Zhejiang Province for Aptamers and Theranostics Zhejiang Cancer HospitalHangzhou Institute of Medicine(HIM)Chinese Academy of SciencesHangzhouZhejiang 310022China molecular Science and Biomedicine Laboratory(MBL) State Key Laboratory of Chemo/Biosensing and ChemometricsCollege of Chemistry and Chemical EngineeringHunan UniversityChangshaHunan 410082China Shanghai Key Laboratory of molecular Imaging Shanghai University of Medicine and Health SciencesShanghai 201318China department of pharmacology and Chemical Biology Shanghai Jiao Tong University School of MedicineShanghai200127China

Serving as targeting ligands,aptamers have shown promise in precision ***,the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’clinical *** bridge this gap,here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68(^(68)Ga)radiolabeled *** specificity and binding affinity of a radiolabeled aptamer,named ^(68)Ga[Ga]-NOTA-SGC8,were maintained as proven in *** preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity,potential mutation risks,or genotoxicity at high dosage(40 mg/kg).Based on this result,a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles,as well as biosafety,of the radiolabeled SGC8 aptamer in the human *** advantage of the cutting-edge total-body PET,the aptamers’distribution pattern in the human body was acquired in a dynamic fashion.

关键词： metabolism dosage Whole

Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128

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Neural Regeneration Research 2024年第11期19卷 2532-2542页

作者： Aina Bellver-Sanchis Pedro AAvila-López Iva Tic David Valle-García Marta Ribalta-Vilella Luis Labrador Deb Ranjan Banerjee Ana Guerrero Gemma Casadesus Coralie Poulard Mercè Pallàs Christian Grinán-Ferré department of pharmacology and Therapeutic chemistry Institut de Neurociències-Universitat de BarcelonaBarcelonaSpain department of Biochemistry and molecular Genetics Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Institute of Biotechnology National Autonomous University of MexicoCuernavacaMexico department of pharmacology and Therapeutics Health Science Center-University of FloridaGainesvilleFLUSA department of chemistry National Institute of Technology DurgapurM G AvenueDurgapurWest BengalIndia Cancer Research Cancer Lyon Universitéde LyonLyonFrance Inserm U1052 Centre de Recherche en Cancérologie de LyonLyonFrance CNRS UMR5286 Centre de Recherche en Cancérlogie de LyonLyonFrance Centro de Investigación en Red Enfermedades Neurodegenerativas(CIBERNED)Instituto de Salud Carlos IIIMadridSpain Neuroimmunology department National Institute of Neurology and Neurosurgery“Manuel Velasco Suárez”Mexico CityMexico

Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative ***,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s ***,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and *** better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor *** found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)***,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control *** also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a *** confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative *** this setting,treatment with G9a inhibitor increases both cell survival and antioxidant ***,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and *** addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers ***,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a ***,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.

关键词： aging cognitive decline epigenetics G9a inhibition microRNAs miR-128 peroxisome-proliferator activator receptorγ(PPARγ) PPARG SAMP8