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SARS-CoV-2 ORF10 hijacking ubiquitination machinery reveals potential unique drug targeting sites

Acta Pharmaceutica Sinica B 2024年第9期14卷 4164-4173页

作者： Kaixiang Zhu Lili Song Linyue Wang Lei Hua Ziyu Luo Tongyun Wang Bo Qin Shuofeng Yuan xiaopan gao Wenyi Mi Sheng Cui NHC Key Laboratory of Systems Biology of Pathogens National Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Key Laboratory of Pathogen Infection Prevention and Control(Peking Union Medical College) Ministry of EducationBeijing 100730China The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)Tianjin Medical University General HospitalDepartment of ImmunologyTianjin Medical UniversityTianjin 300070China Medical School Yan’an UniversityShaanxi ProvinceYan’an 716000China State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SARChina Department of Microbiology Li Ka ShingFaculty of Medicinethe University of Hong KongPokfulamHong Kong SARChina

Viruses often manipulate ubiquitination pathways to facilitate their replication and ***2ZYG11B known as the substrate receptor of cullin-2 RING E3 ligase,is bound by SARS-CoV-2 ORF10 to increase its E3 ligase activity,leading to degradation of IFT46,a protein component of the intraflagellar transport(IFT)complex *** results in dysfunctional cilia,which explains certain symptoms that are specific to ***,the precise molecular mechanism of how ORF10 recognizes CUL2ZYG11B remains ***,we determined the crystal structure of CUL2ZYG11B complexed with the N-terminal extension(NTE)of SARS-CoV-2 ORF10(2.9 A°).The structure reveals that the ORF10 N-terminal heptapeptide(NTH)mimics the Gly/N-degron to bind *** studies identified key residues within ORF10 that are key players in its interaction with CUL2ZYG11B both in ITC assay and in vivo *** addition,we prove that enhancement of CUL2ZYG11B activity for IFT46 degradation by which ORF10-mediated correlates with the binding affinity between ORF10 and ***,we used a Global Protein Stability system to show that the NTH of ORF10 mimics the Gly/N-degron motif,thereby binding competitively to CUL2ZYG11B and inhibiting the degradation of target substrates bearing the Gly/N-degron ***,this study sheds light on how SARS-CoV-2 ORF10 exploits the ubiquitination machinery for proteasomal degradation,and offers valuable insights for optimizing PROTAC-based drug design based on NTH CUL2ZYG11B interaction,while pinpointing a promising target for the development of treatments for COVID-19.

关键词： SARS-CoV-2 ORF10 Crystal structure cullin-2 RING E3 ligase Drug design

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Natural ventilation driven by a restricted heat source elevated to different levels

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Building Simulation 2022年第2期15卷 281-289页

作者： Changqing Yang Wenhao Luo Angui Li xiaopan gao Lunfei Che Lingmin Qiao Teng gao Yubo Liu School of Building Services Science and Engineering Xi'an University of Architecture and TechnologyXi'anShaanxi 710055China China Railway Siyuan Survey and Design Group Co. Ltd.WuhanHubei 430063China Artificial Environment Control Technology Innovation Center of Xi'an University of Architecture and Technology-Yantai YantaiShandong 264006China

The thermal buoyancy generated by the difference in air density in a building can drive hot-pressed natural ventilation,which is an energy-efficient means of ventilation used to obtain higher air ***,the effect of a single-point heat source with limited sides at different heights on stratified flow was studied in a naturally ventilated room in this *** on the classical plume diffusion law of an independent point heat source and the mirroring principle,a calculation model of the thermal stratification height with a restricted source elevated to different levels was derived and *** quantitative effects of the heat source height from the floor,the effective opening area and other factors on the natural ventilation of hot pressure were analyzed.A threshold X_(T)for the separation between a point source and a sidewall was defined to estimate whether the thermal plume was independent or restricted by a *** a method for calculating the threshold xt was *** research can provide a reference basis for designing natural ventilation for buildings with a restricted heat source at different levels to achieve a desired indoor environment.

关键词： stratification height natural ventilation thermal plume restricted heat source different levels

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肺癌患者凝血功能指标变化情况及其与预后的相关性

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临床医学工程 2024年第8期31卷 1025-1026页

作者：彭慧斌韩晓东高小盼安阳市肿瘤医院检验科河南安阳455000 安阳市肿瘤医院外四科河南安阳455000 安阳市肿瘤医院超声医学科河南安阳455000

目的观察肺癌患者的凝血功能指标变化情况及其与预后的关系。方法选取2021年11月至2022年7月我院收治的肺癌患者96例为肺癌组,同期96例身体健康者为健康组,比较两组的凝血功能指标。随访1年,比较不同预后肺癌患者的凝血功能指标,分析预... 详细信息

目的观察肺癌患者的凝血功能指标变化情况及其与预后的关系。方法选取2021年11月至2022年7月我院收治的肺癌患者96例为肺癌组,同期96例身体健康者为健康组,比较两组的凝血功能指标。随访1年,比较不同预后肺癌患者的凝血功能指标,分析预后不良的影响因素。结果肺癌组的APTT、PT均显著短于健康组,FIB、D-D水平均显著高于健康组(P1,P<0.05)。结论肺癌患者普遍伴有凝血功能异常,血液高凝状态是肺癌患者预后不良的影响因素,可用于预后评估。

关键词：肺癌凝血功能预后

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甲状腺癌诊断中超声检查相关影像学征象与患者淋巴结转移的关系

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临床医学工程 2024年第8期31卷 917-918页

作者：高小盼赵佳佳彭慧斌安阳市肿瘤医院超声医学科河南安阳455000 安阳市肿瘤医院外二科河南安阳455000 安阳市肿瘤医院检验科河南安阳455000

目的分析甲状腺癌患者超声检查相关征象与淋巴结转移的关系。方法选择2022年1月至2023年6月我院收治的甲状腺癌患者88例,根据手术病理结果分为转移组和未转移组,比较两组的超声影像学征象,分析甲状腺癌患者发生淋巴结转移的危险因素。... 详细信息

目的分析甲状腺癌患者超声检查相关征象与淋巴结转移的关系。方法选择2022年1月至2023年6月我院收治的甲状腺癌患者88例,根据手术病理结果分为转移组和未转移组,比较两组的超声影像学征象,分析甲状腺癌患者发生淋巴结转移的危险因素。结果转移组的肿瘤直径≥1.5cm、淋巴结内部钙化、血供分级>1级占比均显著高于未转移组(P1,P<0.05)。结论超声影像学征象肿瘤直径、血供分级、淋巴结内部钙化可评估甲状腺癌患者的淋巴结转移风险。

关键词：甲状腺癌超声淋巴结转移影像学征象

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基于FCPN的离散制造系统质量风险分析评估研究

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汽车工艺与材料 2024年第5期 49-58页

作者：赵家黎吴丹郜肖盼代燕霞兰州理工大学机电工程学院兰州730050

针对离散制造系统随机性、多样性以及复杂性的特点,高效、准确地识别系统质量风险因素并进行质量风险量化评估是制定相应质量控制活动、提高产品质量的关键。为此,首先构建模糊着色Petri网的产品质量风险评估模型。然后,确定模糊推理规... 详细信息

针对离散制造系统随机性、多样性以及复杂性的特点,高效、准确地识别系统质量风险因素并进行质量风险量化评估是制定相应质量控制活动、提高产品质量的关键。为此,首先构建模糊着色Petri网的产品质量风险评估模型。然后,确定模糊推理规则,并通过现场获取的置信度经验值进行模糊推理,计算得出中间库所和终止库所的置信度。最后,以汽车顶盖冲压工艺过程为例进行分析,验证了该模型的合理性,并且可推广应用到其他同类离散制造过程。

关键词：离散制造系统顶盖冲压工艺过程模糊着色 Petri 网质量风险评估

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miR-558对肺癌细胞增殖、迁移与凋亡的影响

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中国药业 2024年第11期33卷 57-61页

作者：郭淑娟郑成玲高晓盼孙晓彤阳光融和医院山东潍坊261000 潍坊医学院麻醉学系山东潍坊261000

目的探讨miR-558对肺癌细胞增殖、迁移及凋亡的影响。方法收集医院2020年5月至8月收治的35例肺癌患者的癌组织及其癌旁组织样本,并取对数生长期的人肺癌细胞A549、人支气管上皮细胞BEAS-2B,采用实时荧光定量聚合酶链反应(qPCR)法检测c... 详细信息

目的探讨miR-558对肺癌细胞增殖、迁移及凋亡的影响。方法收集医院2020年5月至8月收治的35例肺癌患者的癌组织及其癌旁组织样本,并取对数生长期的人肺癌细胞A549、人支气管上皮细胞BEAS-2B,采用实时荧光定量聚合酶链反应(qPCR)法检测circ_0001017和miR-558表达水平。取对数生长期的A549细胞进行转染,并分为空质粒(pcDNA)组(A组)、pcDNA-circ_0001017组(B组)、pcDNA-circ_0001017+miR-NC组(C组)、pcDNA-circ_0001017+miR-558组(D组)。采用双荧光素酶报告实验检测circ_0001017与miR-558的靶向关系;采用四甲基偶氮唑盐(MTT)法、平板克隆形成实验、Transwell实验、流式细胞术分别检测细胞的活性、克隆、迁移、凋亡情况;采用qPCR法检测circ_0001017、miR-558表达水平;采用免疫印迹(Westernblot)法检测B细胞淋巴瘤因子-2蛋白(Bcl-2)和Bcl-2相关X蛋白(Bax)的表达水平。结果与癌旁组织比较,肺癌组织中circ_0001017的表达水平显著降低(P<0.05),miR-558的表达水平显著升高(P<0.05);与BEAS-2B细胞比较,A549细胞中circ_0001017的表达水平显著降低(P<0.05),miR-558的表达水平显著升高(P<0.05)。miR-558过表达可显著降低野生型载体(WT)-circ_0001017的荧光素酶活性(P<0.05)。与A组比较,B组细胞的增殖抑制率、凋亡率、circ_0001017和Bax表达水平均显著升高(P<0.05),细胞克隆形成数、迁移细胞数均显著减少(P<0.05),miR-558和Bcl-2表达水平均显著降低(P<0.05);与C组比较,D组细胞的增殖抑制率、凋亡率、circ_0001017和Bax表达水平均显著降低(P<0.05),细胞克隆形成数、迁移细胞数均显著增多(P<0.05),Bcl-2和miR-558表达水平均显著升高(P<0.05)。结论过表达miR-558会减弱过表达circ_0001017对肺癌细胞的增殖、克隆形成、迁移的抑制作用及促细胞凋亡作用。

关键词： circ_0001017 miR-558 肺癌 A549细胞细胞增殖迁移细胞凋亡

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Crystal structure of SARS-CoV-2 papain-like protease

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Acta Pharmaceutica Sinica B 2021年第1期11卷 237-245页

作者： xiaopan gao Bo Qin Pu Chen Kaixiang Zhu Pengjiao Hou Justyna Aleksandra Wojdyla Meitian Wang Sheng Cui NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China The Swiss Light Source(SLS)at the Paul Scherrer Institut Villigen 5232Switzerland

The pandemic of coronavirus disease 2019(COVID-19)is changing the world like never *** crisis is unlikely contained in the absence of effective therapeutics or *** papain-like protease(PLpro)of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)plays essential roles in virus replication and immune evasion,presenting a charming drug *** the PLpro proteases of SARS-CoV-2 and SARS-CoV share significant homology,inhibitor developed for SARS-CoV PLpro is a promising starting point of therapeutic *** this study,we sought to provide structural frameworks for PLpro inhibitor *** determined the unliganded structure of SARS-CoV-2 PLpro mutant C111 S,which shares many structural features of SARS-CoV *** crystal form has unique packing,high solvent content and reasonable resolution 2.5 A°,hence provides a good possibility for fragment-based screening using crystallographic *** characterized the protease activity of PLpro in cleaving synthetic peptide harboring nsp2/nsp3 *** demonstrate that a potent SARS-CoV PLpro inhibitor GRL0617 is highly effective in inhibiting protease activity of SARSCoV-2 with the IC50 of 2.2?0.3 mmol/*** then determined the structure of SARS-CoV-2 PLpro complexed by GRL0617 to 2.6 A°,showing the inhibitor accommodates the S3 e S4 pockets of the substrate binding *** binding of GRL0617 induces closure of the BL2 loop and narrows the substrate binding cleft,whereas the binding of a tetrapeptide substrate enlarges the ***,our results suggest a mechanism of GRL0617 inhibition,that GRL0617 not only occupies the substrate pockets,but also seals the entrance to the substrate binding cleft hence prevents the binding of the LXGG motif of the substrate.

关键词： SARS-CoV-2 PLpro Proteinase inhibitor Crystal structure Antiviral drug Drug design

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Sonodynamic therapy for the treatment of atherosclerosis

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Journal of Pharmaceutical Analysis 2024年第5期14卷 666-677页

作者： Yan Zhang Ying Yang Yudi Feng Xueyan gao Liping Pei xiaopan Li Bingxin gao Lin Liu Chengzeng Wang Shuochen gao The Department of Ultrasound The First Affiliated Hospital of Zhengzhou UniversityZhengzhou450052China The Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou450052China

Atherosclerosis(AS)is a chronic inflammatory disease of large and medium-sized arteries that leads to ischemic heart disease,stroke,and peripheral vascular *** the current treatments,mortality and disability still remain *** therapy(SDT),a non-invasive and localized methodology,has been developed as a promising new treatment for inhibiting atherosclerotic progression and stabilizing *** progress has been made through cell and animal assays,as well as clinical *** example,the effect of SDT on apoptosis and autophagy of cells in AS,especially macrophages,and the concept of non-lethal SDT has also been *** this review,we summarize the ultrasonic parameters and known sonosensitizers utilized in SDT for AS;we elaborate on SDT's therapeutic effects and mechanisms in terms of macrophages,T lymphocytes,neovascularization,smooth muscle cells,lipid,extracellular matrix and efferocytosis within plaques;additionally,we discuss the safety of SDT.A comprehensive summary of the confirmed effects of SDT on AS is conducted to establish a framework for future researchers.

关键词： Atherosclerosis Sonodynamic therapy Sonosensitizer Ultrasound Reactive oxygen species

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Binding of the SARS-CoV-2 spike protein to glycans

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Science Bulletin 2021年第12期66卷 1205-1214,M0004页

作者： Wei Hao Bo Ma Ziheng Li Xiaoyu Wang xiaopan gao Yaohao Li Bo Qin Shiying Shang Sheng Cui Zhongping Tan NHC Key Laboratory of Systems Biology of Pathogens Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Chemistry and Biochemistry and BioFrontiers Institute University of ColoradoBoulder CO 80303USA School of Pharmaceutical Sciences Tsinghua UniversityBeijing W0084China

The pandemic of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused a high number of deaths in the *** combat it,it is necessary to develop a better understanding of how the virus infects host *** normally starts with the attachment of the virus to cell-surface glycans like heparan sulfate(HS)and sialic acid-containing glycolipids/*** this study,we examined and compared the binding of the subunits and spike(S)proteins of SARS-CoV-2,SARS-Co V,and Middle East respiratory disease(MERS)-Co V to these *** results revealed that the S proteins and subunits can bind to HS in a sulfation-dependent manner and no binding with sialic acid residues was ***,this work suggests that HS binding may be a general mechanism for the attachment of these coronaviruses to host cells,and supports the potential importance of HS in infection and in the development of antiviral agents against these viruses.

关键词： SARS-CoV-2 S protein Heparan sulfate Glycan microarray Surface plasmon resonance Sulfation Sialic acid

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Targeting papain-like protease for broad-spectrum coronavirus inhibition

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Protein & Cell 2022年第12期13卷 940-953页

作者： Shuofeng Yuan xiaopan gao Kaiming Tang Jian-Piao Cai Menglong Hu Peng Luo Lei Wen Zi-Wei Ye Cuiting Luo Jessica Oi-Ling Tsang Chris Chun-Yiu Chan Yaoqiang Huang Jianli Cao Ronghui Liang Zhenzhi Qin Bo Qin Feifei Yin Hin Chu Dong-Yan Jin Ren Sun Jasper Fuk-Woo Chan Sheng Cui Kwok-Yung Yuen State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Microbiology Li Ka ShingFaculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Molecular and Medical Pharmacology David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCAUSA Key Laboratory of Tropical Translational Medicine of Ministry of Education Hainan Medical UniversityHaikou 571199China Academician Workstation of Hainan Province Hainan Medical UniversityHaikou 571199China Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases The University of Hong KongPokfulamHong Kong Special Administrative RegionChina Guangzhou Laboratory Guangzhou 510320China Department of Clinical Microbiology and Infection Control The University of Hong Kong-Shenzhen HospitalShenzhen 518053China

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral *** the multi-functional papain-like protease(PLpro)domain of the viral nsp3 holds ***,none of the known coronavirus PLpro inhibitors has been shown to be in vivo ***,we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity,including against the Sarbecoviruses(SARSCoV-1 and SARS-CoV-2),Merbecovirus(MERS-CoV),as well as the Alphacoronavirus(hCoV-229E and hCoVOC43).Importantly,F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice.F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage,as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase *** the significant difference of substrate recognition,mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue,whereas an allosteric inhibitor of MERSPLpro interacting with its 271E *** proof-ofconcept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anticoronavirus *** orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.

关键词： protease inhibitor coronavirus Nsp3 antiviral

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