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

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 crisis.Although 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 compromised.Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses.Cathepsin L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response.Here,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and CAPN1.The 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 CAPN1.Both 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 cells.Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance.Moreover,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in mice.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 model.And 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 pneumonia.Taken together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

关键词： calpain overcome entrance

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The raphe nuclei are the early lesion site of gastric α-synuclein propagation to the substantia nigra

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2057-2076页

作者： Chenglu zhang ruxue Bo Tiantian Zhou Naihong Chen Yuhe Yuan State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Chinese Academy of Medical Sciences&Peking Union Medical College Institute of Materia MedicaBeijing 100050China

Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with PD.Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy.Although the“gut–brain”hypothesis is proposed to explain the underlying mechanism,where the earlier lesioned site in the brain of gastricα-synuclein and howα-synuclein further spreads are not fully understood.Here we report that caudal raphe nuclei(CRN)are the early lesion site of gastricα-synuclein propagating through the spinal cord,while locus coeruleus(LC)and substantia nigra pars compacta(SNpc)were further affected over a time frame of 7 months.Pathologicalα-synuclein propagation via CRN leads to neuron loss and disordered neuron activity,accompanied by abnormal motor and non-motor behavior.Potential neuron circuits are observed among CRN,LC,and SNpc,which contribute to the venerability of dopaminergic neurons in SNpc.These results show that CRN is the key region for the gastricα-synuclein spread to the midbrain.Our study provides valuable details for the“gut–brain”hypothesis and proposes a valuable PD model for future research on early PD intervention.

关键词： Raphe nuclei α-Synuclein Gastrointestinal tract Electrophysiology Locus coeruleus Substantia nigra pars compacta Parkinson's disease Spinal cord

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Oral remdesivir derivative VV116 is a potent inhibitor of respiratory syncytial virus with efficacy in mouse model

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1386-1388页

作者： ruxue zhang Yumin zhang Wei Zheng Weijuan Shang Yan Wu Ning Li Jun Xiong Hualiang Jiang Jingshan Shen Gengfu Xiao Yuanchao Xie Leike zhang State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China University of Chinese Academy of Sciences Beijing 100049China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China Shanghai Junshi Biosciences Co. Ltd.Shanghai 200126China Lingang Laboratory Shanghai 200031China

Dear Editor,Respiratory syncytial virus(RSV)is the leading cause of serious lower respiratory tract disease in children under 5 years of age worldwide,causing an estimated 3.2 million hospitalizations and 120,000 deaths in children globally per year.Furthermore,nearly all children can be infected with RSV by 2 years of age,and individuals can be repeatedly re-infected with RSV throughout life,which poses great threats to infants,the elderly.

关键词： respiratory syncytial repeatedly

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Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332

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Protein & Cell 2022年第9期13卷 689-693页

作者： Yao Zhao Chao Fang Qi zhang ruxue zhang Xiangbo Zhao Yinkai Duan Haofeng Wang Yan Zhu Lu Feng Jinyi Zhao Maolin Shao Xiuna Yang Leike zhang Chao Peng Kailin Yang Dawei Ma Zihe Rao Haitao Yang Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Bioorganic&Natural Products Chemistry Center for Excellence in Molecular SynthesisShanghai Institute of Organic ChemistryUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200032China CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China National Facility for Protein Science in Shanghai Zhangjiang LabShanghai Advanced Research InstituteChinese Academy of SciencesShanghai 201210China Taussig Cancer Center Cleveland ClinicClevelandOH 44195USA Laboratory of Structural Biology School of Life Sciences and School of MedicineTsinghua UniversityBeijing 100091China State Key Laboratory of Medicinal Chemical Biology Frontiers Science Center for Cell ResponseCollege of Life SciencesNankai Universityand Tianjin Key Laboratory of Protein SciencesTianjin 300071China

Dear Editor,Since December 2019,the pandemic of coronavirus disease 2019(COVID-19)has taken a heavy toll on global health,creating an urgent need to develop effective strategies for prevention and treatment.The etiological agent,known as severe acute respiratory syndrome coronavirus 2(SARSCoV-2),has infected nearly 229.2 million people worldwide with more than 4.7 million deaths as of September 15,2021.Older age and preexisting health conditions are associated with worse clinical prognosis including higher mortality rates(Zhou et al.,2020).The global race to combat this pandemic has led to rapid deployment of numerous effective vaccines against SARS-CoV-2(Tregoning et al.,2021).However,the emergence of viral variants,including the Delta variant(B.1.617.2),compromised vaccine effectiveness with resurgence of SARS-CoV-2 infection among highly vaccinated population(Keehner et al.,2021).Therefore,development of therapeutics against the more conserved viral targets would be essential to contain the spread of COVID-19 and reduce mortality.

关键词： mortality prevention Crystal

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80 Gbit/s PAM4光接收机低噪声模拟前端电路设计

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微电子学 2024年第2期54卷 201-206页

作者：张春茗王浩宋茹雪西安邮电大学电子工程学院

采用UMC 28 nm CMOS工艺，设计了一款应用于光接收机、工作在80 Gbit/s PAM4的低噪声模拟前端电路（AFE）。对噪声和带宽进行折中设计，采用了跨阻放大器（TIA）级联连续时间线性均衡器（CTLE）技术和输入电感峰化技术。为了更好地控制... 详细信息

采用UMC 28 nm CMOS工艺，设计了一款应用于光接收机、工作在80 Gbit/s PAM4的低噪声模拟前端电路（AFE）。对噪声和带宽进行折中设计，采用了跨阻放大器（TIA）级联连续时间线性均衡器（CTLE）技术和输入电感峰化技术。为了更好地控制低频增益，进一步拓展带宽，采用了跨导跨阻（gm-TIA）结构的VGA。在输入电容100 fF和供电电压1.2 V下，实现的跨阻增益为48.5 dBΩ,带宽为36.1 GHz,平均等效输入噪声电流为■,功耗为14.5 mW。

关键词： PAM4编码跨阻放大器级联连续时间线性均衡器可变增益放大器

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电力大数据技术在智能电网的实践应用

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电力设备管理 2024年第4期 95-97页

作者：张阳敬如雪张霞侯天玉国网甘肃省电力公司武威供电公司

智能电网是新一代电网技术发展的重要方向,对促进我国经济社会发展和满足人们美好生活需要具有重要意义。电力大数据是智能电网的重要组成部分,通过大数据技术的应用,可以实现电力企业各类资源的有效整合和优化配置,对推动智能电网建设... 详细信息

智能电网是新一代电网技术发展的重要方向,对促进我国经济社会发展和满足人们美好生活需要具有重要意义。电力大数据是智能电网的重要组成部分,通过大数据技术的应用,可以实现电力企业各类资源的有效整合和优化配置,对推动智能电网建设具有重要作用。基于此,本文对电力大数据技术在智能电网中的应用进行探讨,提出基于电力大数据技术的智能电网架构及关键技术,并分析电力大数据在智能电网中的实践应用。

关键词：电力大数据智能电网实践应用

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基于Bayesian模型的电力大数据在生态环境监管中的应用策略优化研究

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电力系统装备 2024年第1期 171-173,176页

作者：敬如雪侯天玉张霞国网武威供电公司甘肃武威733000

随着社会快速发展和工业化进程加速,环境污染问题日益凸显,加强环境监管与治理刻不容缓。现有的环境监管方法难以准确及时地监测和预测环境污染情况。文章利用Bayesian模型分析排污企业用电量,以监测和预测区域环境污染情况。并选取我... 详细信息

随着社会快速发展和工业化进程加速,环境污染问题日益凸显,加强环境监管与治理刻不容缓。现有的环境监管方法难以准确及时地监测和预测环境污染情况。文章利用Bayesian模型分析排污企业用电量,以监测和预测区域环境污染情况。并选取我国西北某区域的排污企业用电数据作为研究对象开展实证分析,将预测结果与实际环境污染数据进行对比,展示了该方法在实际应用中的效果和可行性,为实现更精细化的环境保护和监管提供了一种新颖的方法和思路。

关键词： Bayesian模型电力大数据环境监管预测优化策略

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增加湿法磷酸萃取槽气相空间高度改造

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生态产业科学与磷氟工程 2024年第4期39卷 35-37页

作者：陈望张儒学严世科云南三环中化化肥有限公司生产维保部

针对湿法磷酸萃取槽顶衬胶短期内出现鼓包、碳化、脱落，钢筋混凝土被腐蚀、槽顶冒浓烟的问题，企业普遍采用降低溢流口以增加气相空间高度来解决该问题。在不打破原有闪冷系统平衡的基础上，将萃取槽溢流口形状从倒三角形改为长方形，... 详细信息

针对湿法磷酸萃取槽顶衬胶短期内出现鼓包、碳化、脱落，钢筋混凝土被腐蚀、槽顶冒浓烟的问题，企业普遍采用降低溢流口以增加气相空间高度来解决该问题。在不打破原有闪冷系统平衡的基础上，将萃取槽溢流口形状从倒三角形改为长方形，并降低溢流口最低点高度，气相空间高度由1.266～1.717 m增加到1.812～2.054 m，解决了萃取槽出现的问题。

关键词：湿法磷酸萃取槽溢流高度气相空间高度

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Remaining True to the Original Aspiration and Striving to Improve the Teaching Effect of the Current Ideological and Political Course

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Asian Agricultural Research 2020年第1期12卷 68-71页

作者： Jiarui XU Lu CHEN ruxue zhang School of Education Central China Normal UniversityWuhan 430079China

At present,there are a series of relatively difficult problems in the ideological and political course of colleges and universities.In the face of complicated situation,we still need keeping original intention and mission,calmly dealing with the challenges from all sides,and exploring the opportunities contained therein.Meanwhile,we should grasp the overall situation in a macro sense,and use top level design to layout and plan change strategy.

关键词： Colleges and universities Ideological and political course Teaching reform Teaching effect

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基于SAX-ARMA模型混合模型的企业排污用电监测

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电力系统装备 2024年第1期 163-167页

作者：侯天玉敬如雪张凌薇国网武威供电公司甘肃武威733000

随着社会的快速发展和工业化进程的加速,环境污染问题日益凸显,加强环境监管与治理成为刻不容缓的任务。为了有效地控制企业排污,提高环境质量,利用电力数据易获取、数据量大等特点,通过多种算法研究,使得企业排污用电预测更精准,实现... 详细信息

随着社会的快速发展和工业化进程的加速,环境污染问题日益凸显,加强环境监管与治理成为刻不容缓的任务。为了有效地控制企业排污,提高环境质量,利用电力数据易获取、数据量大等特点,通过多种算法研究,使得企业排污用电预测更精准,实现企业排污用电的精确监测。文章旨在利用企业排污用电数据,结合ARMA算法和SAX算法的优势,构建SAX-ARMA混合模型,对企业排污用电进行监测预警。实例分析选取特定区域的排污企业用电数据作为研究对象,将预测结果与实际数据进行对比,并与设定的阈值进行对比,展示了该方法在实际应用中的效果和可行性,实现排污企业的短期排污数据预测,从而加强对重点企业污染防治的联防联控。通过对比分析ARMA模型和SAX-ARMA混合模型的预测结果,和模型的评估指标的值,发现SAX-ARMA混合模型比ARMA模型的预测值和真实值的重合程度更高,且SAX-ARMA混合模型的RMSE和MAPE的值比ARMA模型分别低0.151和3.304,综上所述SAX-ARMA混合模型更适合文章的研究内容。

关键词： SAX-ARMA 电力大数据环保排污

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