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

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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Visualization of nasal powder distribution using biomimetic human nasal cavity model

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Acta Pharmaceutica Sinica B 2024年第1期14卷 392-404页

作者： Jiawen Su yan Liu Hongyu Sun Abid Naeem Huipeng Xu Yue Qu Caifen Wang Zeru Li Jianhua Lu Lulu Wang Xiaofeng Wang Jie Wu Lixin Sun Jiwen Zhang Zhigang Wang Rui yang Li Wu key laboratory of Modern Preparation of TCM Ministry of EducationJiangxi University of Chinese MedicineNanchang 330004China key laboratory of Molecular Pharmacology and drug Evaluation School of PharmacyMinistry of EducationYantai UniversityYantai 264005China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201210China Nantong Haimen People’s Hospital Nantong 226199China yangtze Delta drug Advanced Research Institute Nantong 226126China Shenyang Pharmaceutical University Shenyang 110016China National Institutes for Food and drug Control Beijing 100000China Nanjing University of Chinese Medicine Nanjing 210023China

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal ***,no reliable method is currently available to assess its impact on delivery *** this study,a biomimetic nasal model based on three-dimensional(3D)reconstruction and three-dimensional printing(3DP)technology was developed for visualizing the deposition of drug powders in the nasal *** results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and *** nasal cavity model was modified with dimethicone and validated to be suitable for the deposition *** experimental device produced the most satisfactory results with five spray ***,particle sizes and spray angles were found to significantly affect the experimental device’s performance and alter drug distribution,***,mometasone furoate(MF)nasal spray(NS)distribution patterns were investigated in a goat nasal cavity model and three male goat noses,confirming the in vitro and in vivo *** conclusion,the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution.

关键词： Nasal drug deposition Nasal drug distribution Nasal drug delivery Biomimetic nasal model Nasal powder Three-dimensional reconstruction Three-dimensional printing Nasal drug distribution

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Gut liver brain axis in diseases:the implications for therapeutic interventions

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Signal Transduction and Targeted Therapy 2024年第1期9卷 79-104页

作者： Mengyao yan Shuli Man Benyue Sun Long Ma Lanping Guo Luqi Huang Wenyuan Gao State key laboratory of Food Nutrition and Safety Key Laboratory of Industrial MicrobiologyMinistry of EducationTianjin Key Laboratory of Industry MicrobiologyNational and Local United Engineering Lab of Metabolic Control Fermentation TechnologyChina International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal ChemistryCollege of BiotechnologyTianjin University of Science&Technology300457 TianjinChina National Resource Center for Chinese Materia Medica China Academy of Chinese Medical Sciences100700 BeijingChina Tianjin key laboratory for Modern drug Delivery&High-Efficiency School of Pharmaceutical Science and TechnologyTianjin UniversityWeijin Road300072 TianjinChina

Gut-liver-brain axis is a three-way highway of information interaction system among the gastrointestinal tract,liver,and nervous *** the past few decades,breakthrough progress has been made in the gut liver brain axis,mainly through understanding its formation mechanism and increasing treatment *** this review,we discuss various complex networks including barrier permeability,gut hormones,gut microbial metabolites,vagus nerve,neurotransmitters,immunity,brain toxic metabolites,β-amyloid(Aβ)metabolism,and epigenetic regulation in the gut-liver-brain *** therapies containing antibiotics,probiotics,prebiotics,synbiotics,fecal microbiota transplantation(FMT),polyphenols,low FODMAP diet and nanotechnology application regulate the gut liver brain ***,some special treatments targeting gut-liver axis include farnesoid X receptor(FXR)agonists,takeda G protein-coupled receptor 5(TGR5)agonists,glucagon-like peptide-1(GLP-1)receptor antagonists and fibroblast growth factor 19(FGF19)*** gut-brain axis embraces cognitive behavioral therapy(CBT),antidepressants and tryptophan metabolism-related *** liver-brain axis contains epigenetic regulation and Aβmetabolism-related *** the future,a better understanding of gut-liver-brain axis interactions will promote the development of novel preventative strategies and the discovery of precise therapeutic targets in multiple diseases.

关键词： metabolism therapeutic immunity

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Mechanistic research:Selenium regulates virulence factors,reducing adhesion ability and inflammatory damage of Helicobacter pylori

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World Journal of Gastroenterology 2024年第1期30卷 91-107页

作者： Chun Qin Gan-Rong Huang Ai-Xing Guan Wen-Ting Zhou Hao Chen Pei-Pei Luo Xian-Ke Luo yan-Qiang Huang Zan-Song Huang Guangxi Technology innovation Cooperation Base of Prevention and Control Pathogenic Microbes with drug Resistance Youjiang Medical University for NationalitiesBaise 533000Guangxi Zhuang Autonomous RegionChina Department of Digestive Diseases Affiliated Hospital of Youjiang Medical University for NationalitiesBaise 533000Guangxi Zhuang Autonomous RegionChina key laboratory of the Prevention and Treatment of drug Resistant microbial Infecting Youjiang Medical University for NationalitiesBaise 533000Guangxi Zhuang Autonomous RegionChina Department of Pathology Wannan Medical CollegeWuhu 241002Anhui ProvinceChina Department of Gastroenterology Wujin People’s Hospital affiliated to Jiangsu UniversityChangzhou 213004Jiangsu ProvinceChina Department of Gastroenterology Guangzhou Liwan District People's HospitalGuangzhou 510370Guangdong ProvinceChina

BACKGROUND The pathogenicity of Helicobacter pylori is dependent on factors including the environment and the *** selenium is closely related to pathogenicity as an environmental factor,the specific correlation between them remains *** To investigate how selenium acts on virulence factors and reduces their *** *** strains were induced by sodium *** expression of cytotoxin-associated protein A(CagA)and vacuolating cytotoxin gene A(VacA)was determined by quantitative PCR and Western *** was used to analyze CagA,CagM,CagE,Cag1,Cag3,and CagT.C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction,and *** colonization,inflammatory reactions,and the cell adhesion ability of *** were *** CagA and VacA expression was upregulated at first and then downregulated in the *** strains after sodium selenite *** expression was significantly and steadily downregulated after the 5th cycle(10 d).Transcriptome analysis revealed that sodium selenite altered the levels affect *** virulence factors such as CagA,CagM,CagE,Cag1,Cag3,and *** these factors,CagM and CagE expression was continuously downregulated and further downregulated after 2 h of induction with sodium ***,CagT expression was upregulated before the 3rd cycle(6 d)and significantly downregulated after the 5th ***1 and Cag3 expression was upregulated and downregulated,respectively,but no significant change was observed by the 5th cycle.C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite *** extent of *** colonization in the stomach increased;however,sodium selenite also induced a mild inflammatory reaction in the gastric mucosa of ***-infected mice,and the cell adhesion ability of *** was significantly *** These results demonstrate that *** displayed virulence attenuation after

关键词： Helicobacter pylori Sodium selenite Virulence factors Adherence Inflammation

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A near-infrared fluorescent probe for visualizing transformation pathway of Cys/Hcy and H2S and its applications in living system

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Chinese Chemical Letters 2024年第5期35卷 296-301页

作者： Yudi Cheng Xiao Wang Jiao Chen Zihan Zhang Jiadong Ou Mengyao She Fulin Chen Jianli Li key laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education Xi’an Key Laboratory of Functional Supramolecular Structure and MaterialsCollege of Chemistry&Materials ScienceNorthwest UniversityXi’an 710127China key laboratory of Resource Biology and Biotechnology in Western China Ministry of EducationBiomedicine Key Laboratory of Shaanxi ProvinceLab of Tissue Engineeringthe College of Life SciencesFaculty of Life Science&MedicineNorthwest UniversityXi’an 710069China

Sulfydryl-contained(-SH)substances including hydrogen sulfide(H_(2)S),cysteine(Cys),homocysteine(Hcy)and glutathione(GSH)play crucial roles in living systems,and their variations are closely associated with various ***,we developed a near-infrared intramolecular charge transfer(ICT)based fluorescent probe Y-NBD,achieving detection of Cys/Hcy and H_(2)S with different fluorescent signals(green-red for Cys/Hcy,red for H_(2)S),large Stokes shifts(∼100/105nm or 191 nm)and high signal-background-ratio,but not responding to GSH.Y-NBD was successfully applied to image exogenous/endogenous Cys/Hcy and H_(2)S in various living cancer cells(HeLa,A549,and HepG2)and in *** not only visualized the transformation pathway of several thiols in HepG2 cells but also verified that the intestine is the main site for the activation and metabolism of Y-NBD in zebrafish,as well as realized to evaluate the degree of drug-induced liver *** work provides a promising tool for imaging Cys/Hcy and H_(2)S in living systems and shows great potency in evaluating drug-induced liver injury and its treatment.

关键词： Fluorescent probe Near-infrared Hydrogen sulfide Cysteine/homocysteine Large Stokes shift Dicyanoisophorone drug-induced liver injury

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High-throughput fluorescent screening of thioredoxin reductase inhibitors to inhibit Mycobacterium tuberculosis

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Chinese Chemical Letters 2024年第3期35卷 358-362页

作者： Fei yan Xin Zhao Ruibo Li Xiuyan Han Qiulong yan Lei Feng Xiulan Xin Jingnan Cui Xiaochi Ma Second Affiliated Hospital Dalian Medical UniversityDalian 116044China State key laboratory of Fine Chemicals Dalian University of TechnologyDalian 116024China Jiangsu key laboratory of New drug Research and Clinical Pharmacy Xuzhou Medical UniversityXuzhou 221004China School of Chemistry and Chemical Engineering Henan Normal UniversityXinxiang 453007China College of Bioengineering Beijing PolytechnicBeijing 100029China

Tuberculosis(TB)is a chronic infectious disease,which is caused by the pathogen Mycobacterium tuberculosis(Mtb)and reemerged as a global health risk with a significant proportion of multi-drug resistant and extensively drug resistant TB *** is very urgent to find some novel high-confidence drug targets in Mtb for discovering the effective anti-TB *** reductase(TrxR)has been identified to be a highly viable target for anti-TB drugs for its important role in protecting the pathogen from thiol-specific oxidizing stress,regulating intracellular dithiol/disulfide homeostasis and DNA replication and *** the present work,a near-infrared(NIR)fluorescent probe DDAT was developed for the detection of TrxR activity and used to high-throughput screen the TrxR inhibitors from natural *** screened TrxR inhibitors from Sappan Lignum and microbial metabolites that were further used to inhibit Mycobacterium *** the results indicate that DDAT is a practical fluorescent molecular tool for the discovery of potential anti-TB drugs.

关键词： Thioredoxin reductase NIR fluorescent probe Fluorescence imaging High-throughput screening inhibitors Inhibit Mycobacterium tuberculosis

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Tumor-targeted self-assembled micelles reducing PD-L1 expression combined with ICIs to enhance chemo-immunotherapy of TNBC

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Chinese Chemical Letters 2024年第2期35卷 305-310页

作者： Hongda Zhu Kai Ma Rui Ruan Chaobo yang Aqin yan Jing Li Qi Yu Hongmei Sun Mingxing Liu Hongmei Zheng Jing Gao Xiaofang Guan Zhu Dai Yao Sun Cooperative innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province) Key Laboratory of Fermentation Engineering (Ministry of Education)National “111” Center for Cellular Regulation and Molecular PharmaceuticsSchool of Food and Biological EngineeringHubei University of TechnologyWuhan 430068China Hubei Cancer Hospital Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430079China National key laboratory of Green Pesticide College of ChemistryCentral China Normal UniversityWuhan 430079China key laboratory of Medical Optics Suzhou Institute of Biomedical Engineering and TechnologyChinese Academy of SciencesSuzhou 215163China key laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science Ministry of EducationQingdao University of Science and TechnologyQingdao 266000China

Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of ***,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive *** results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of *** micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.

关键词： Immunotherapy Tumor-targeted Self-assembled micelles Metformin Reducing PD-L1 expression TNBC

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Simple and versatile in situ thermo-sensitive hydrogel for rectal administration of SZ-A to alleviate inflammation and repair mucosal barrier in ulcerative colitis

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Chinese Chemical Letters 2024年第6期35卷 462-468页

作者： Yu yan Jiawei Song Dongdong Liu Zihan Liu Jialing Cheng Zhiyang Chen yanfang yang Weizhe Jiang Hongliang Wang Jun Ye Yuling Liu State key laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China College of Pharmacy Guangxi Medical UniversityNanning 530021China Beijing key laboratory of drug Delivery Technology and Novel Formulation Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Ulcerative colitis(UC)is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon and disrupted intestinal *** mori(Sangzhi)alkaloids(SZ-A),derived from twigs of mulberry,were approved by the National Medical Products Administration in 2020 for treating type 2 diabetes *** evidence has confirmed that SZ-A also alleviates non-alcoholic fatty liver disease and ameliorates inflammation,indicating its potential to address inflammation in ***,the treatment of UC faces challenges due to low drug delivery efficiency and short retention *** overcome these challenges,an injectable and adherent in-situ thermo-sensitive hydrogel containing SZ-A was developed for rectal drug delivery,utilizing the thermo-sensitive polymers Poloxamer 407and *** thermo-sensitive hydrogel system was designed with a moderate gelation temperature of 32±0.5℃,a short gelation time of 64 s,a p H range of 7-10,high moisturizing capability exceeding 90%,and moderate mechanical strength of 4-5 *** a rat model with UC,the in situ thermo-sensitive hydrogel significantly extended the retention time at the colonic site and enabled sustained release after rectal *** of UC were markedly reduced following rectal administration of SZ-A thermosensitive ***,the release of inflammatory factors,such as interleukin-1β(IL-1β),IL-6,IL-18,tumor necrosis factor-α(TNF-α),and transforming growth factor-β1(TGF-β1),significantly decreased in the SZ-A thermo-sensitive hydrogel *** integrity of the colonic mucosal barrier was significantly enhanced following the application of SZ-A thermo-sensitive *** conclusion,rectal administration of SZ-A in situ thermo-sensitive hydrogel effectively alleviated UC symptoms,inhibited the secretion of inflammatory factors,and promoted the repair of the colonic mucosal *** approach holds promise as a potential treatment for UC.

关键词： Ulcerative colitis SZ-A Thermo-sensitive hydrogel Rectal administration Alleviation of inflammation Mucosal barrier repair

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An Efficient Probe for Bacterial Nitroreductase Imaging and Detection Based on NanoLuc-Furimazine Bioluminescent Pair

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Chinese Journal of Chemistry 2024年第12期42卷 1373-1380页

作者： Ximeng Shi Yumeng Wang Jiaoyang Yu Yating yang Zecheng Jin Hanghang Wang Dalei Wu Wei Chen Jianming Guo Yinan Zhang Jiangsu key laboratoryforFunctional Substances of Chinese Medicine School of PharmacyNanjing Universityof Chinese MedicineNanjingJiangsu210023China Jiangsu Collaborative innovation Center of Chinese Medicinal Resources Industrialization School of PharmacyNanjing University of ChineseMedicineNanjingJiangsu210023China Clinical Research Center the Second Hospital of NanjingAffiliated Hospital to Nanjing University of Chinese MedicineNanjingJiangsu210003China key laboratory of Resources Biology and Biotechnology in Western China Ministry of EducationCollege of Life SciencesNorthwestUniversityXi'anShaanxi710069China Helmholtz International Lab State Key Laboratoryof Microbial TechnologyShandong UniversityQingdaoShandong 266237China

Comprehensive SummaryThe detection of critical endogenous species, such as bacteria in microenvironments in the body, requires better imaging tools for visualization and monitoring of biological events. Bioluminescence imaging is the most popular strategy for obtaining real-time in living cells and organisms. Herein, we introduced a nitroaryl group on the C-3 position and a hydroxy group at the C-6 phenyl ring on furimazine to report the first bioluminescent probe (7) based on NanoLuc-furimazine bioluminescent pair for the detection of nitroreductase in bacteria. The probe, which possessed up to 560-fold intensity increase with a low detection limit of 16 ng/mL of nitroreductase, has the most efficient uncage efficiency in comparison with other bioluminescent congeners, thus enabling highly selective and sensitive visualization of NTR activity in a panel of clinical priority pathogens. Additionally, imaging of the recombinant strain as well as the NTR from mouse feces indicated the potential of this probe in the application of different mouse disease models.

关键词： Nitroreductase NanoLuc-furimazine Biosensors Analytical methods Luminescence Imaging agents

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Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1651-1664页

作者： Xiong Xie Qiaoshuai Lan Jinyi Zhao Sulin Zhang Lu Liu Yumin Zhang Wei Xu Maolin Shao Jingjing Peng Shuai Xia yan Zhu Keke Zhang Xianglei Zhang Ruxue Zhang jian Li Wenhao Dai Zhen Ge Shulei Hu Changyue Yu Jiang Wang Dakota Ma Mingyue Zheng Haitao yang Gengfu Xiao Zihe Rao Lu Lu Leike Zhang Fang Bai Yao Zhao Shibo Jiang Hong Liu drug Discovery and Design Center State Key Laboratory of Drug ResearchCAS Key Laboratory of Receptor ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China key laboratory of Medical Molecular Virology(MOE/NHC/CAMS) School of Basic Medical SciencesShanghai Institute of Infectious Disease and BiosecurityFudan UniversityShanghai 200032China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State key laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China School of Chinese Materia Medica Nanjing University of Chinese Medicine138 Xian Lin RoadJiangsu 210023 NanjingChina School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China National Clinical Research Center for Infectious Disease Shenzhen Third People's HospitalShenzhen 518112China

Respiratory disease caused by coronavirus infection remains a global health *** several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be ***-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging *** L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune ***,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and *** X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of *** showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various *** mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral ***,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in *** addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse *** 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute *** together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with anti

关键词： calpain overcome entrance

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