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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

Combination therapy with oncolytic virus and T cells or mRNA vaccine amplifies antitumor effects

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2655-2668页

作者： rao Fu Ruoyao Qi Hualong Xiong Xing Lei Yao Jiang Jinhang He Feng Chen Liang Zhang Dekui Qiu Yiyi Chen Meifeng Nie Xueran Guo Yuhe Zhu Jinlei Zhang Mingxi Yue Jiali Cao Guosong Wang Yuqiong Que Mujing Fang Yingbin Wang Yixin Chen Tong cheng Shengxiang ge Jun Zhang Quan Yuan Tianying Zhang Ningshao Xia State Key Laboratory of Vaccines for Infectious Diseases Xiang An Biomedicine LaboratoryDepartment of Laboratory MedicineSchool of Public Health&School of Life SciencesXiamen UniversityXiamen 361102 FujianChina National Institute of Diagnostics and Vaccine Development in Infectious Diseases Xiamen 361102 FujianChina

Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years,but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used *** this study,an oncolytic virus(rVSV-LCMVG)that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T *** transforming the immunosuppressive tumor microenvironment into an immunosensitive one,in B16 tumor-bearing mice,combination therapy showed superior antitumor effects than *** occurred whether the OV was administered intratumorally or *** therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8^(+)T cells to the TME to trigger antitumor immune *** with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment,downregulating the expression of PD-1,and restoring effector T-cell *** offer a combination therapy with greater translational value,mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T *** combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged *** study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens,in terms of synergistic efficacy and mechanism.

关键词： transferred rational boosting

涡轮叶片前缘强化旋流–气膜复合高效冷却研究

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工程热物理学报 2024年第10期45卷 3101-3110页

作者：李菲栾勇饶宇程宇立上海交通大学机械与动力工程学院上海200240 上海交通大学深圳研究院深圳518000

本文建立了ge-E3高压涡轮第一级动叶前缘复合冷却模型,利用流热固耦合传热方法数值研究了冲击–气膜复合冷却和旋流–气膜复合冷却的流动换热特性,考虑了实际主流对前缘复合冷却效果的影响。在此基础上提出了内部凸脊通道的强化旋流–... 详细信息

本文建立了ge-E3高压涡轮第一级动叶前缘复合冷却模型,利用流热固耦合传热方法数值研究了冲击–气膜复合冷却和旋流–气膜复合冷却的流动换热特性,考虑了实际主流对前缘复合冷却效果的影响。在此基础上提出了内部凸脊通道的强化旋流–气膜复合冷却新型结构,分析了不同吹风比下前缘冷却模型的流场结构和传热分布。结果表明:在研究范围内,与冲击冷却相比,旋流冷却具有更均匀的传热分布和更低的压力损失;旋流在光滑内壁的冷却通道中平均努塞尔数可以提升17.6%以上,前缘平均综合冷效可以提升4.7%~7.2%,冷气端压力损失可降低4.7%~5.1%;而凸脊结构进一步强化了旋流冷却,内部冷却通道的平均努塞尔数可以显著提升37.7%以上,平均综合冷效可以提升6.1%~11.8%,压损可降低3.9%~4.1%。

关键词：涡轮叶片前缘冲击冷却旋流–气膜复合冷却冷却强化耦合传热

Research on the development methodology for clinical practice guidelines for organic integration of traditional Chinese medicine and Western medicine

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Military Medical Research 2024年第3期11卷 313-322页

作者： Ying-Hui Jin Yan-Ping Wang Ying-Lan Xie Gui-Hua Tian Xiao-Yu Zhang Nan-Nan Shi Ke-Hu Yang Xin Sun Yao-Long Chen Da-Rong Wu Xin-Feng Guo Long ge Chen Zhao cheng Lu Yin Jiang Jing Guo Si-Yu Yan Yong-Bo Wang Qiao Huang Xiang-Ying Ren Ying-Yue rao Yun-Yun Wang Meng-Qian Yuan Xian-Tao Zeng Hong-Cai Shang Center for Evidence-Based and Translational Medicine Zhongnan Hospital of Wuhan UniversityWuhan 430071China Institute of Basic Research in Clinical Medicine China Academy of Chinese Medical SciencesBeijing 100700China China Center for Evidence Based Traditional Chinese Medicine Beijing 100029China Hubei Provincial Hospital of Traditional Chinese Medicine Wuhan 430074China Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing Dongzhimen HospitalBeijing University of Chinese MedicineBeijing 100700China Evidence-Based Medicine Center School of Basic Medical SciencesLanzhou UniversityLanzhou 730000China China Center for Evidence-Based Medicine West China Hospital of Sichuan UniversityChengdu 610041China State Key Laboratory of Dampness Syndrome of Chinese Medicine the Second Affliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510120China Evidence-based Medicine Team Guangdong Provincial Hospital of Traditional Chinese MedicineGuangzhou 510120China Nanjing University of Chinese Medicine Nanjing 210023China Jiangsu Province Hospital of Chinese Medicine Nanjing 210029China

Integrated traditional Chinese medicine(TCM)and Western medicine(WM)is a new medical science grounded in the knowledge bases of both TCM and WM,which then forms a unique modern medical system in *** TCM and WM has a long history in China,and has made important achievements in the process of clinical diagnosis and ***,the methodological defects in currently published clinical practice guidelines(CPGs)limit its *** organic integration of TCM and WM is a deeper integration of TCM and *** realize the progression of"integration"to"organic integration",a targeted and standardized guideline development methodology is ***,the purpose of this study is to establish a standardized development procedure for clinical practice guidelines for the organic integration of TCM and WM to promote the systematic integration of TCM and WM research results into clinical practice guidelines in order to achieve optimal results as the whole is greater than the sum of the parts.

关键词： Methodology Traditional Chinese medicine Western medicine Organic integration Clinical practice guidelines(CPGs)

The newly emerged SARS-Like coronavirus HCoV-EMC also has an “Achilles’ heel”: current effective inhibitor targeting a 3C-like protease

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Protein & Cell 2013年第4期4卷 248-250页

作者： Zhilin Ren Liming Yan Ning Zhang Yu Guo cheng Yang Zhiyong Lou zihe rao College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300071China Structural Biology Laboratory and MOE Laboratory of Protein Science School of Medicine and Life ScienceTsinghua UniversityBeijing 100084China National Laboratory of Macromolecules Institute of BiophysicsChinese Academy of ScienceBeijing 100101China Emerging Infection Disease Program High-throughput Molecular Drug Discovery CenterTianjin Joint Academy of Biomedicine and TechnologyTianjin 300457China

From the global outbreak of SARS-CoV caused infection disease in 2003,coronaviruses(CoVs)are known to be a great threat to the human ***,a new SARS-like coronavirus,human betacoronavirus 2c EMC/2012(HCoV-EMC),has been identified and the appearance of this new CoV raises concerns that a new spread of CoV may occurs in the *** solving the crystal structure of HCoV-EMC main protease with a wide-spectrum anti-CoV inhibitor N3,we confi rmed that that N3 blocks the function of HCoV-EMC main protease through a similar mechanism to other *** with the good pharmaceutical features,N3 is conceivable to be effective to HCoV-EMC and other CoVs appearing in the *** fi ndings make it convincing that CoVs will not be a threat to human health.

关键词： EMC SARS Together

谷氨酰胺在重症急性胰腺炎营养治疗中的研究进展

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医学综述 2024年第16期30卷 1995-1998页

作者：贾鸽程梓荷陈婧刘伯恒王胜昱西安医学院第一附属医院呼吸与危重症医学科西安710077 西安交通大学医学院西安710061

重症急性胰腺炎(SAP)是一种复杂的炎症性疾病,其病情发展迅速,发病症状种类繁多,可在短时间内造成人体多个器官不同程度损伤,严重威胁患者的生命健康。营养支持是SAP治疗的重要环节,免疫营养调控在其中发挥重要作用。谷氨酰胺(Gln)是重... 详细信息

重症急性胰腺炎(SAP)是一种复杂的炎症性疾病,其病情发展迅速,发病症状种类繁多,可在短时间内造成人体多个器官不同程度损伤,严重威胁患者的生命健康。营养支持是SAP治疗的重要环节,免疫营养调控在其中发挥重要作用。谷氨酰胺(Gln)是重要的免疫营养添加剂,但目前关于谷氨酰胺使用剂量、时机及营养途径等方面仍存在争议。因此,深入研究Gln在SAP营养治疗中的作用机制,可以为疾病的治疗提供新思路。

关键词：重症急性胰腺炎谷氨酰胺应用剂量营养时机营养途径

Architecture of severe fever with thrombocytopenia syndromevirus

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Protein & Cell 2023年第12期14卷 914-918页

作者： Zixian Sun Jing cheng Yuan Bai Lin Cao Daoxin Xie Fei Deng Xinzheng Zhang zihe rao Zhiyong Lou Department of Basic Research Guangzhou LaboratoryGuangzhou 510005China MOE Key Laboratory of Protein Science School of MedicineTsinghua UniversityBeijing 100084China University of Chinese Academy of Sciences Beijing100049China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China National Virus Resource Center Wuhan Institute of VirologyChinese Academy of SciencesWuhan 430071China State Key Laboratory of Medicinal Chemical Biology and College of Life Science and Pharmacy Nankai UniversityTianjin 300350China

Dear Editor,Severe fever with thrombocytopenia syndrome(SFTS)is an acute infectious disease caused by severe fever with thrombocytopenia syndrome virus(SFTSV)and is characterized by rapid onset,high mortality and widespread *** fatality rate can be as high as 10%-30%,which is significantly higher than that of the hemorrhagic fever caused by Hantavirus in the same area(Song et al.,2018).However,no effective treatments or vaccines are available yet,and the underlying pathogenic mechanisms of the virus are poorly understood.

关键词： fever mortality

A structural view of the antibiotic degradation enzyme NDM-1 from a superbug

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Protein & Cell 2011年第5期2卷 384-394页

作者： Yu Guo Jing Wang Guojun Niu Wenqing Shui Yuna Sun Honggang Zhou Yaozhou Zhang cheng Yang Zhiyong Lou zihe rao High-throughput Molecular Drug Discovery Center Tianjin Joint Academy of Biotechnology and MedicineTianjin 300071China Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China College of Life Science Nankai UniversityTianjin 300074China National Laboratory of Macromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China

Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1(NDM-1)are a type of newly discovered antibioticresistant *** rapid pandemic spread of NDM-1 bacteria worldwide(spreading to India,Pakistan,Europe,America,and Chinese Taiwan)in less than 2 months characterizes these microbes as a potentially major global health *** drug resistance of NDM-1 bacteria is largely due to plasmids containing the blaNDM-1 gene shuttling through bacterial *** NDM-1 enzyme encoded by the blaNDM-1 gene hydrolyzes β-lactam antibiotics,allowing the bacteria to escape the action of *** the biological functions and structural features of NDM-1 have been proposed according to results from functional and structural investigation of its homologues,the precise molecular characteristics and mechanism of action of NDM-1 have not been ***,we report the threedimensional structure of NDM-1 with two catalytic zinc ions in its active *** and mass spectroscopy results revealed that D-captopril can effectively inhibit the enzymatic activity of NDM-1 by binding to its active site with high binding *** unique features concerning the primary sequence and structural conformation of the active site distinguish NDM-1 from other reported metallo-β-lactamases(MBLs)and implicate its role in wide spectrum drug *** also discuss the molecular mechanism of NDM-1 action and its essential role in the pandemic of drug-resistant NDM-1 *** results will provide helpful information for future drug discovery targeting drug resistance caused by NDM-1 and related metallo-β-lactamases.

关键词： New Delhi metallo-β-lactamase 1(NDM-1) drug resistance crystal structure drug discovery

Insight into the Ebola virus nucleocapsid assembly mechanism： crystal structure of Ebola virus nucleoprotein core domain at 1.8 A resolution

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Protein & Cell 2015年第5期6卷 351-362页

作者： Shishang Dong Peng Yang Guobang Li Baocheng Liu Wenming Wang Xiang Liu Boran Xia cheng Yang Zhiyong Lou Yu Guo zihe rao State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy Nankai University Tianjin 300071 China College of Life Sciences Nankai University Tianjin 300071 China Tianjin International Joint Academy of Biotechnology & Medicine Tianjin 300457 China

Ebola virus （EBOV） is a key member of Filoviridae family and causes severe human infectious diseases with high morbidity and mortality. As a typical negative-sense single-stranded RNA （-ssRNA） viruses, EBOV possess a nucleocapsid protein （NP） to facilitate genomic RNA encapsidation to form viral ribonucleoprotein complex （RNP） together with genome RNA and polymerase, which plays the most essential role in virus proliferation cycle. However, the mechanism of EBOV RNP formation remains unclear. In this work, we solved the high resolution structure of core domain of EBOV NP. The polypeptide of EBOV NP core domain （NPcore） pos- sesses an N-lobe and C-lobe to clamp a RNA binding groove, presenting similarities with the structures of the other reported viral NPs encoded by the members from Mononegavirales order. Most strikingly, a hydrophobic pocket at the surface of the C-lobe is occupied by an a- helix of EBOV NPcore itself, which is highly conserved among filoviridae family. Combined with other bio- chemical and biophysical evidences, our results provides great potential for understanding the mechanism underlying EBOV RNP formation via the mobility of EBOV NP element and enables the development of antiviral therapies targeting EBOV RNP formation.

关键词： Filoviridae Ebola virus nucleoprotein nucleocapsid crystal structure assembly mechanism