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| 1 | Structures of EV71 RNA-dependent RNA polymerase in complex with substrate and analogue provide a drug target against the hand-foot-and-mouth disease pandemic in China显示文摘Enterovirus 71(EV71),one of the major causative agents for hand-foot-and-mouth disease(HFMD),has caused more than 100 deaths among Chinese children since March 2008.The EV71 genome encodes an RNAdependent RNA polymerase(RdRp),denoted 3D^(pol),which is central for viral genome replication and is a key target for the discovery of specific antiviral therapeutics.Here we report the crystal structures of EV71 RdRp(3D^(pol))and in complex with substrate guanosine-5'-triphosphate and analog 5-bromouridine-5'-triphosphate best to 2.4Åresolution.The structure of EV71 RdRp(3D^(pol))has a wider open thumb domain compared with the most closely related crystal structure of poliovirus RdRp.And the EV71 RdRp(3D^(pol))complex with GTP or Br-UTP bounded shows two distinct movements of the polymerase by substrate or analogue binding.The model of the complex with the template:primer derived by superimposition with foot-and-mouth disease virus(FMDV)3D/RNA complex reveals the likely recognition and binding of template:primer RNA by the polymerase.These results together provide a molecular basis for EV71 RNA replication and reveal a potential target for anti-EV71 drug discovery. | Yang Wu Zhiyong Lou Yi Miao Yue Yu Hui Dong Wei Peng Mark Bartlam Xuemei Li Zihe Rao | 2010 | Protein & Cell2010，1，5： | 30 |
| 2 | A structural view of the antibiotic degradation enzyme NDM-1 from a superbug显示文摘Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1(NDM-1)are a type of newly discovered antibioticresistant bacteria.The 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 problem.The drug resistance of NDM-1 bacteria is largely due to plasmids containing the blaNDM-1 gene shuttling through bacterial populations.The NDM-1 enzyme encoded by the blaNDM-1 gene hydrolyzes β-lactam antibiotics,allowing the bacteria to escape the action of antibiotics.Although 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 clarified.Here,we report the threedimensional structure of NDM-1 with two catalytic zinc ions in its active site.Biological 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 affinity.The 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 resistance.We also discuss the molecular mechanism of NDM-1 action and its essential role in the pandemic of drug-resistant NDM-1 bacteria.Our results will provide helpful information for future drug discovery targeting drug resistance caused by NDM-1 and related metallo-β-lactamases. | Yu Guo Jing Wang Guojun Niu Wenqing Shui Yuna Sun Honggang Zhou Yaozhou Zhang Cheng Yang Zhiyong Lou Zihe Rao | 2011 | Protein & Cell2011，2，5： | 16 |
| 3 | Molecular mechanism of SCARB2-mediatec attachment and uncoating of EV71显示文摘 | Minghao Dang Xiangxi Wang Quan Wang Yaxin Wang Jianping Lin Yuna Sun Xuemei Li Liguo Zhang Zhiyong Lou Junzhi Wang Zihe Rao | 2014 | Protein & Cell2014，5，9： | 13 |
| 4 | The binding of a monoclonal antibody to the apical region of SCARB2 blocks EV71 infection显示文摘(EV71 ) Entero 病毒 71 引起手,脚,和嘴疾病(HFMD ) 并且偶尔导致严重神经病学的复杂并发症甚至死亡。(SCARB2 ) Scavenger 受体班 B 成员 2 是为 EV71 的功能的受体,调停病毒的附件,成为主观,和 uncoating。然而, SCARB2 上的 EV71 的准确有约束力的地点是未知的。在这研究,我们产生了绑在人然而并非老鼠 SCARB2 的 monoclonal 抗体(mAb ) 。它被称为 JL2,并且它能有效地禁止目标房间的 EV71 感染。用人和老鼠 SCARB2 的一套怪物,我们鉴别包含人的 SCARB2 的残余 77-113 的区域显著地作出贡献到 JL2 绑定。SCARB2-JL2 建筑群的结构表明 JL2 绑在包含 -helices 的 SCARB2 的顶端的区域 2, 5,和 14。我们的结果在 SCARB2 和 EV71 入口的分子的机制上为 EV71 提供新卓见进潜在的有约束力的地点。 | Xuyuan Zhang Pan Yang Nan Wang Jialong Zhang Jingyun Li Hao Guo Xiangyun Yin Zihe Rao Xiangxi wang Liguo Zhang | 2017 | Protein & Cell2017，8，8： | 10 |
| 5 | The newly emerged SARS-Like coronavirus HCoV-EMC also has an “Achilles’ heel”: current effective inhibitor targeting a 3C-like protease显示文摘From the global outbreak of SARS-CoV caused infection disease in 2003,coronaviruses(CoVs)are known to be a great threat to the human health.Recently,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 future.By 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 CoVs.Together with the good pharmaceutical features,N3 is conceivable to be effective to HCoV-EMC and other CoVs appearing in the future.These fi ndings make it convincing that CoVs will not be a threat to human health. | Zhilin Ren Liming Yan Ning Zhang Yu Guo Cheng Yang Zhiyong Lou Zihe Rao | 2013 | Protein & Cell2013，4，4： | 10 |
| 6 | Crystal structure of cytotoxin protein suilysin from Streptococcus suis显示文摘Cholesterol-dependent cytolysins(CDC)are pore forming toxins.A prototype of the CDC family members is perfringolysin O(PFO),which directly binds to the cell membrane enriched in cholesterol,causing cell lysis.However,an exception of this general observation is intermedilysin(ILY)of Streptococcus intermedius,which requires human CD59 as a receptor in addition to cholesterol for its hemolytic activity.A possible explanation of this functional difference is the conformational variation between the C-terminal domains of the two toxins,particularly in the highly conserved undecapeptide termed tryptophan rich motif.Here,we present the crystal structure of suilysin,a CDC toxin from the infectious swine pathogen Streptococcus suis.Like PFO,suilysin does not require a host receptor for hemolytic activity;yet the crystal structure of suilysin exhibits a similar conformation in the tryptophan rich motif to ILY.This observation suggests that the current view of the structure-function relationship between CDC proteins and membrane association is far from complete. | Lingfeng Xu Bo Huang Huamao Du Xuejun CZhang Jianguo Xu Xuemei Li Zihe Rao | 2010 | Protein & Cell2010，1，1： | 9 |
| 7 | Insight into the Ebola virus nucleocapsid assembly mechanism: crystal structure of Ebola virus nucleoprotein core domain at 1.8 A resolution显示文摘 | Shishang Dong Peng Yang Guobang Li Baocheng Liu Wenming Wang Xiang Liu Boran Xia Cheng Yang Zhiyong Lou Yu Guo Zihe Rao | 2015 | Protein & Cell2015，6，5： | 6 |
| 8 | Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332显示文摘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. | 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 | 2022 | Protein & Cell2022，13，9： | 6 |
| 9 | TIM-1 acts a dual-attachment receptor for Ebolavirus by interacting directly with viral GP and the PS on the viral envelope显示文摘Ebolavirus 能与 50%90% 的死亡率在人引起出血性的发烧。当前,没有同意的疫苗和抗病毒的治疗是可得到的。人的 TIM1 为 EBOV 被看作一个附件因素,提高通过和位于病毒的信封的 PS 的相互作用的病毒的感染。然而,推理由 filovirus 位于 hTIM-1,然而并非另外的 PS 有约束力的受体的更好的用法下面,未知的遗体。我们第一在 vitro 表明了在 hTIM-1 和 EBOV GP 之间的一个直接相互作用并且决定了 hTIM-1 和 hTIM-4 的 Ig V 领域的水晶结构。在到 EBOV GP 的 hTIM-1 的有约束力的区域被怪物和变化试金印射,它基于结构的分析被设计。象点异种一样用 hTIM-1 和它的相当或相同的事物执行的 Pseudovirion 感染试金在 EBOV 细胞的入口验证了 GP 有约束力的地点和 EBOV GP-hTIM-1 相互作用的重要性的地点。 | Shuai Yuan Lei Cao Hui Ling Minghao Dang Yao Sun Xuyuan Zhang Yutao Chen Liguo Zhang Dan Su Xiangxi Wang Zihe Rao | 2015 | Protein & Cell2015，6，11： | 6 |
| 10 | MCP-1-induced protein-1,an immune regulator显示文摘MCP-1-induced protein-1(MCPIP1)is a newly identified protein that is crucial to immune regulation.Mice lack-ing MCPIP1 gene suffer from severe immune disorders,and most of them cannot survive longer than 12 weeks.Considerable progress has been made in revealing the mechanism underlying the immune regulatory function of MCPIP1.MCPIP1 can act as an RNase to promote the mRNA degradation of some inflammatory cytokines,such as IL-6 and IL-1.Pre-microRNAs are also confirmed to be the substrate of MCPIP1 RNase.The structure of MCPIP1 N-terminal conserved domain shows a PilT N-terminus-like RNase structure,further supporting the notion that MCPIP1 has RNase activity.MCPIP1 can also deubiquitinate TNF receptor-associated factor family proteins,which are known to mediate immune and inflammatory responses.In this review,we summarize recent progress on the immune regulatory role of MCPIP1 and discuss the mechanisms underlying its function. | Jiwei Xu Sheng Fu Wei Peng Zihe Rao | 2012 | Protein & Cell2012，3，12： | 6 |
| 11 | Architecture of the herpesvirus genomepackaging complex and implications for DNA translocation显示文摘Genome packaging is a fundamental process in a viral life cycle and a prime target of antiviral drugs.Herpesviruses use an ATP-driven packaging motor/terminase complex to translocate and cleave concatemeric dsDNA into procapsids but its molecular architecture and mechanism are unknown.We report atomic structures of a herpesvirus hexameric terminase complex in both the apo and ADP·BeF3-bound states.Each subunit of the hexameric ring comprises three components-the ATPase/terminase pUL15 and two regulator/fixer proteins,pUL28 and pUL33-unlike bacteriophage terminases.Distal to the nuclease domains,six ATPase domains form a central channel with conserved basicpatches conducive to DNA binding and trans-acting arginine fingers are essential to ATP hydrolysis and sequential DNA translocation.Rearrangement of the nuclease domains mediated by regulatory domains converts DNA translocation mode to cleavage mode.Our structures favor a sequential revolution model for DNA translocation and suggest mechanisms for concerted domain rearrangements leading to DNA cleavage. | Yunxiang Yang Pan Yang Nan Wang Zhonghao Chen Dan Su ZHong Zhou Zihe Rao Xiangxi Wang | 2020 | Protein & Cell2020，11，5： | 5 |
| 12 | High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors显示文摘A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identify new anti-COVID-19 agents.In this study,we screened over 6,000 compounds that included approved drugs,drug candidates in clinical trials,and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease(PLpro).Together with main protease(Mpro),PLpro is responsible for processing the viral replicase polyprotein into functional units.There-fore,it is an attractive target for antiviral drug develop-ment.Here we discovered four compounds,YM155,cryptotanshinone,tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 pmol/L.These compounds also exhibit strong antiviral activities in cell-based assays.YM155,an anti-cancer drug candidate in clinical trials,has the most potent antiviral activity with an EC50 value of 170 nmol/L.In addition,we have determined the crystal structures of this enzyme and its complex with YM155,revealing a unique binding mode.YM155 simultaneously targets three'hot'spots on PLpro,including the substrate-binding pocket,the interferon stimulating gene product 15(ISG15)binding site and zinc finger motif.Our results demonstrate the efficacy of this screening and repur-posing strategy,which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments. | Yao Zhao Xiaoyu Du Yinkai Duan Xiaoyan Pan Yifang Sun Tian You Lin Han Zhenming Jin Weijuan Shang Jing Yu Hangtian Guo Qianying Liu Yan Wu Chao Peng Jun Wang Chenghao Zhu Xiuna Yang Kailin Yang Ying Lei Luke W.Guddat Wenqing Xu Gengfu Xiao Lei Sun Leike Zhang Zihe Rao Haitao Yang | 2021 | Protein & Cell2021，12，11： | 4 |
| 13 | An open conformation determined by a structural switch for 2A protease from coxsackievirus A16显示文摘Coxsackievirus A16 belongs to the family Picornaviridae,and is a major agent of hand-foot-and-mouth disease that infects mostly children,and to date no vaccines or antivi-ral therapies are available.2A protease of enterovirus is a nonstructural protein and possesses both self-cleavage activity and the ability to cleave the eukaryotic translation initiation factor 4G.Here we present the crystal structure of coxsackievirus A162A protease,which interestingly forms hexamers in crystal as well as in solution.This structure shows an open conformation,with its active site accessible,ready for substrate binding and cleav-age activity.In conjunction with a previously reported“closed”state structure of human rhinovirus 2,we were able to develop a detailed hypothesis for the conforma-tional conversion triggered by two“switcher”residues Glu88 and Tyr89 located within the bll2-cII loop.Substrate recognition assays revealed that amino acid residues P1′,P2 and P4 are essential for substrate specificity,which was verifi ed by our substrate binding model.In addition,we compared the in vitro cleavage effi ciency of 2A pro-teases from coxsackievirus A16 and enterovirus 71 upon the same substrates by fl uorescence resonance energy transfer(FRET),and observed higher protease activity of enterovirus 71 compared to that of coxsackievirus A16.In conclusion,our study shows an open conformation of coxsackievirus A162A protease and the underlying mechanisms for conformational conversion and substrate specifi city.These new insights should facilitate the future rational design of effi cient 2A protease inhibitors. | Yao Sun Xiangxi Wang Shuai Yuan Minghao Dang Xuemei Li Xuejun CZhang Zihe Rao | 2013 | Protein & Cell2013，4，10： | 3 |
| 14 | Structural basis of Zika virus helicase in recognizing its substrates显示文摘Zika 的最近的爆炸爆发病毒(ZIKV ) 感染在南方和中美洲和加勒比海被报导了。与 ZIKV 感染联系的新生的头小畸型已经引起了国际担心的一种公共健康紧急情况。没有特定的疫苗或药当前是可得到的治疗 ZIKV 感染。ZIKV helicase,在病毒的 RNA 复制起一个枢轴的作用,是为治疗的一个吸引人的目标。我们决定了 ZIKV helicase-ATP-Mn 2+ 和 ZIKV helicase-RNA 的水晶结构。这是到 ATP 的任何 flavivirus helicase 界限的第一结构。有相关 flavivirus helicases 的比较证明了尽管在活跃地点的批评 P 环在不同种类之中有可变符合构造,认出 ATP/Mn 2+ 采用一个相同模式。ZIKV helicase-RNA 的结构表明了在 RNA 绑定之上,马达领域的旋转能引起重要 conformational 变化。惊人地,尽管 ZIKV 和登革热病毒(DENV ) apo-helicases 份额为 RNA 绑定保存了残余,他们在为 RNA 识别的不同单个模式的马达域旋转结果的不同礼貌。它建议 flavivirus helicases 能发展了一台保存引擎为 RNA 放松,而是不同马达领域旋转从 nucleoside triphosphate 把化学能变换成机械精力在可变 RNA 识别的结果适应单个病毒的复制的模式。 | Hongliang Tian Xiaoyun Ji Xiaoyun Yang Zhongxin Zhang zuoku Lu Kailin Yang Cheng Chen Qi Zhao Heng Chi Zhongyu Mu Wei Xie Zefang Wang Huiqiang Lou Haitao Yang Zihe Rao | 2016 | Protein & Cell2016，7，8： | 3 |
| 15 | High-level expression and secondary structure analysis of the bovine mature prion protein显示文摘By using the recombinant DNA technology, the gene of the bovine mature prion protein bPrPcL) has been cloned into pET30a and the resulting plasmid has been expressed in E.coli BL21(DE3). After solubilizing in 8 mol/L urea, the expression product was purified by cation ion exchange chromatography. The purified product was refolded by dilution and the recovery was about 15%. Analysis of mass spectrum, circular dichroism (CD) spectrum and Fourier transform infrared (FTIR) spectrum demonstrate that the molecular weight of the bPrPcL is 23 630 u, the bPrPcL has a high α-helix content (36.1%) and low (3-sheet content (11.9%). | WANG Dawei YANG Huaiyi RAO Zihe TIAN Bo | 2000 | Chinese Science Bulletin2000，45，14： | 3 |
| 16 | Double lock of a potent human therapeutic monoclonal antibody against SARS-CoV-2显示文摘Receptor recognition and subsequent membrane fusion are essential for the establishment of successful infection by SARS-CoV-2.Halting these steps can cure COVID-19.Here we have identified and characterized a potent human monoclonal antibody,HB27,that blocks SARS-CoV-2 attachment to its cellular receptor at sub-nM concentrations.Remarkably,HB27 can also prevent SARS-CoV-2 membrane fusion.Consequently,a single dose of HB27 conferred effective protection against SARS-CoV-2 in two established mouse models.Rhesus macaques showed no obvious adverse events when administrated with10 times the effective dose of HB27.Cryo-EM studies on complex of SARS-CoV-2 trimeric S with HB27 Fab reveal that three Fab fragments work synergistically to occlude SARS-CoV-2 from binding to the ACE2 receptor.Binding of the antibody also restrains any further conformational changes of the receptor binding domain,possibly interfering with progression from the prefusion to the postfusion stage.These results suggest that HB27 is a promising candidate for immuno-therapies against COVID-19. | Ling Zhu Yong-Qiang Deng Rong-Rong Zhang Zhen Cui Chun-Yun Sun Chang-Fa Fan Xiaorui Xing Weijin Huang Qi Chen Na-Na Zhang Qing Ye Tian-Shu Cao Nan Wang Lei Wang Lei Cao Huiyu Wang Desheng Kong Juan Ma Chunxia Luo Yanjing Zhang Jianhui Nie Yao Sun Zhe Lv Neil Shaw Qianqian Li Xiao-Feng Li Junjie Hu Liangzhi Xie Zihe Rao Youchun Wang Xiangxi Wang Cheng-Feng Qin | 2021 | National Science Review2021，8，3： | 3 |
| 17 | Crystal structure of the African swine fever virus structural protein p35 reveals its role for core shell assembly显示文摘Dear Editor,The African swine fever(ASF)is a highly contagious hemorrhagic and lethal disease in domestic pigs.The ASF outbreaks of in many Asia countries,including China,Vietnam,Mongolia,and South Korea,have posed a huge threat to the pig indusry.In the attempt to stop ASF from spreading further in China's Mainland,more than 10 million pigs have been culled since August 2018.The causative agent for ASF is a DNA virus,African swine fever virus(ASFV).Although this deadly disease has been reported in Kenya nearly one hundred years ago,there has been no vaccine for protection from ASFV infection or effective treatments to cure ASF until now. | Guobang Li Dan Fu Guangshun Zhang Dongming Zhao Mingyu Li Xue Geng Dongdong Sun Yuhui Wang Cheng Chen Peng Jiao Lin Cao Yu Guo Zihe Rao | 2020 | Protein & Cell2020，11，8： | 3 |
| 18 | Structure of African swine fever virus p15 reveals its dual role for membrane-association and DNA binding显示文摘Dear Editor, African swine fever (ASF) is a highly contagious disease of domestic pigs caused by African swine fever virus (ASFV),with mortality rates approaching 90%-100%.The first ASF case was described in 1921 in Kenya.Over the past decades, ASF has spread from Sub-Saharan Africa to Europe and Asia, and pose a huge threat to global food safety.Since the first ASF case reported in August 2018, more than 10 million pigs had been culled in China at an enormous economic loss.The risk of ASFV mutating to infect humans is extremely low.However, ASF not only threatens food security but also severely strikes the world economy in many fields, such as the global supply of the blood thinner heparin,most of which is produced from pigs.Hence, ASF is a strictly monitored infectious animal disease by OIE (World Organization for Animal Health), unfortunately, there is no approved drug or vaccine against this lethal viral disease. | Dan Fu Dongming Zhao Wei Zhang Guangshun Zhang Mingyu Li Zheng Zhang Yuhui Wang Dongdong Sun Peng Jiao Cheng Chen Yu Guo Zihe Rao | 2020 | Protein & Cell2020，11，8： | 3 |
| 19 | Structures of the portal vertex reveal essential protein-protein interactions for Herpesvirus assembly and maturation显示文摘Dear Editor,Herpesviridae is a large family of double-stranded DNA(dsDNA)viruses that cause a variety of human diseases ranging from cold sores and chicken pox to congenital defects,blindness and cancer(Chayavichitsilp et al.,2009;Wang et al.,2018).In the past 70 years,substantial advances in our knowledge of the molecular biology of herpesviruses have led to insights into disease pathogenesis and management.However,the mechanism for capsid assembly that requires the ordered packing of about 4,000 protein subunits into the hexons,pentons and triplexes remains elusive.It is still a puzzle how initially identical subunits adopt both hexameric and pentameric conformations in the capsid and select the correct locations needed to form closed shells of the proper size.Biochemical and genetic studies have shown that the portal is involved in initiation of capsid assembly(Newcomb et al.,2005)and functions akin to a DNA-sensor coupling genome-packaging achieved by a genome-packaging machinery-“terminase complex”(Chen et al.,2020;Yunxiang Yang,2020)with icosahedral capsid maturation(Lokareddy et al.,2017).Structural investigations of the herpesvirus portal have proven challenging due to the small size of this dodecamer,which accounts for less than 1%of the total mass of the capsid protein layer and the technical difficulties involved in resolving non-icosahedral components of such large icosahedral viruses(diameter is∼1,250Å).Efforts of many investigators over two decades have made to reconstruct the cryo-electron microscopy(cryo-EM)structure of herpesvirus portal vertex and more recently near-atomic structures of two herpesvirus(herpes simplex virus type 1(HSV-1)and Kaposi’s sarcoma-associated herpesvirus(KSHV))portal vertices were reported(McElwee et al.,2018;Gong et al.,2019;Liu et al.,2019). | Nan Wang Wenyuan Chen Ling Zhu Dongjie Zhu Rui Feng Jialing Wang Bin Zhu Xinzheng Zhang Xiaoqing Chen Xianjie Liu Runbin Yan Dongyao Ni Grace Guoying Zhou Hongrong Liu Zihe Rao Xiangxi Wang | 2020 | Protein & Cell2020，11，5： | 2 |
| 20 | Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy显示文摘Hepatitis C virus(HCV)is a leading cause of liver disease worldwide.Although several HCV protease/polymerase inhibitors were recently approved by U.S.FDA,the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistanee.Viral entry is an essential target step for antiviral development,but FDA-approved HCV entry inhibitor remains exclusive.Here we identify serotonin 2A receptor(5-HT2aR)is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy.The silencing of 5-HT2aR and clinically available 5-HT2aR antagonist suppress cell culture-derived HCV(HCVcc)in different liver cells and primary human hepatocytes at late endocytosis process.The mechanism is related to regulate the correct plasma membrane localization of claudin 1(CLDN1).Moreover,phenoxybenzamine(PBZ),an FDAapproved 5-HT2aR antagonist,inhibits all major HCV genotypes in vitro and displays synergy in combination with clinical used anti-HCV drugs.The impact of PBZ on HCV genotype 2a is documented in immune-competent humanized transgenic mice.Our results not only expand the understanding of HCV entry,but also present a promising target for the invention of HCV entry inhibitor. | Lin Cao Jizheng Chen Yaxin Wang Yuting Yang Jie Qing Zihe Rao Xinwen Chen Zhiyong Lou | 2019 | Protein & Cell2019，10，3： | 2 |
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