The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SA...The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug development.In this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell model.Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation.Ciclopirox induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower mobility.These condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP expression.Our results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.展开更多
The Coronavirus Disease 2019(COVID-19)caused by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)is a global pandemic that seriously threatens health and socioeconomic development,but the existed antiviral d...The Coronavirus Disease 2019(COVID-19)caused by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)is a global pandemic that seriously threatens health and socioeconomic development,but the existed antiviral drugs and vaccines still cannot yet halt the spread of the epidemic.Therefore,a comprehensive and profound understanding of the pathogenesis of SARS-CoV-2 is urgently needed to explore effective therapeutic targets.Here,we conducted a multiomics study of SARS-CoV-2-infected lung epithelial cells,including transcriptomic,proteomic,and ubiquitinomic.Multiomics analysis showed that SARS-CoV-2-infected lung epithelial cells activated strong innate immune response,including interferon and inflammatory responses.Ubiquitinomic further reveals the underlying mechanism of SARS-CoV-2 disrupting the host innate immune response.In addition,SARS-CoV-2 proteins were found to be ubiquitinated during infection despite the fact that SARS-CoV-2 itself didn’t code any E3 ligase,and that ubiquitination at three sites on the Spike protein could significantly enhance viral infection.Further screening of the E3 ubiquitin ligases and deubiquitinating enzymes(DUBs)library revealed four E3 ligases influencing SARS-CoV-2 infection,thus providing several new antiviral targets.This multiomics combined with high-throughput screening study reveals that SARS-CoV-2 not only modulates innate immunity,but also promotes viral infection,by hijacking ubiquitination-specific processes,highlighting potential antiviral and anti-inflammation targets.展开更多
基金supported by grants from Shenzhen Science and Technology Program(Grant No.JCYJ20220530163206015,China)National Key Research and Development Program of China(Grant No.2021YFA0910900)+4 种基金Shenzhen Science and Technology Program(Grant No.JCYJ20220818103017036,China)the National Science Fund for Distinguished Young Scholars(Grant No.82025022,China)Guangdong Basic and Applied Basic Research Foundation(Grant No.2023A1515110033,China)Guangdong Science and Technology Plan Project,construction of high-level biosafety laboratories(Grant No.2021B1212030010,China)Guangdong Basic and Applied Basic Research Foundation(Grant No.2023A1515110033,China).
文摘The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug development.In this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell model.Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation.Ciclopirox induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower mobility.These condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP expression.Our results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.
基金supported in part by the National key research and development program(2021YFC2300103)the National Natural Science Foundation of China(82101857,82151212)+4 种基金the National Science Fund for Distinguished Young Scholars(82025022)the Guangdong Provincial Department of Science and Technology(2021B1212030010)the Shenzhen Science and Technology Innovation Committee(KQTD20200909113758004)the Central Charity Fund of Chinese Academy of Medical Science(2020-PT310-009)Guangzhou Lab Emerging Funding(EKPG21-03).
文摘The Coronavirus Disease 2019(COVID-19)caused by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)is a global pandemic that seriously threatens health and socioeconomic development,but the existed antiviral drugs and vaccines still cannot yet halt the spread of the epidemic.Therefore,a comprehensive and profound understanding of the pathogenesis of SARS-CoV-2 is urgently needed to explore effective therapeutic targets.Here,we conducted a multiomics study of SARS-CoV-2-infected lung epithelial cells,including transcriptomic,proteomic,and ubiquitinomic.Multiomics analysis showed that SARS-CoV-2-infected lung epithelial cells activated strong innate immune response,including interferon and inflammatory responses.Ubiquitinomic further reveals the underlying mechanism of SARS-CoV-2 disrupting the host innate immune response.In addition,SARS-CoV-2 proteins were found to be ubiquitinated during infection despite the fact that SARS-CoV-2 itself didn’t code any E3 ligase,and that ubiquitination at three sites on the Spike protein could significantly enhance viral infection.Further screening of the E3 ubiquitin ligases and deubiquitinating enzymes(DUBs)library revealed four E3 ligases influencing SARS-CoV-2 infection,thus providing several new antiviral targets.This multiomics combined with high-throughput screening study reveals that SARS-CoV-2 not only modulates innate immunity,but also promotes viral infection,by hijacking ubiquitination-specific processes,highlighting potential antiviral and anti-inflammation targets.
