Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern  

作　　者：Ilaria Frasson Linda Diamante Manuela Zangrossi Elena Carbognin Anna Dalla Pietà Alessandro Penna Antonio Rosato Ranieri Verin Filippo Torrigiani Cristiano Salata Marìa Paula Dizanzo Lorenzo Vaccaro Davide Cacchiarelli Sara N.Richter Marco Montagner Graziano Martello 

机构地区：[1]Department of Molecular Medicine,University of Padua,Padua 35121,Italy [2]Department of Biology,Armenise/Harvard Pluripotent Stem Cell Biology Laboratory,University of Padua,Padua 35131,Italy [3]Department of Surgery,Oncology and Gastroenterology,University of Padua,Padua 35128,Italy [4]Veneto Institute of Oncology IOV-IRCCS,Padua 35128,Italy [5]Department of Comparative Biomedicine and Food Science,University of Padua,Padua 35020,Italy [6]Telethon Institute of Genetics and Medicine(TIGEM),Armenise/Harvard Laboratory of Integrative Genomics,Pozzuoli 80078,Italy [7]Department of Translational Medicine,University of Naples Federico II,Naples 80138,Italy [8]School for Advanced Studies,Genomics and Experimental Medicine Program,University of Naples Federico II,Naples 80138,Italy [9]Microbiology and Virology Unit,Padua University Hospital,Padua 35128,Italy

出　　处：《Journal of Molecular Cell Biology》2024年第3期9-23,共15页分子细胞生物学报（英文版）

基　　金：supported by the CaRiPaRo Foundation(NewTarCoV2);the Ministry of Education,University and Research(PRIN-2020KSY3KL);supported by the Telethon Foundation Core Grant,European Research Council(ERC)(CellKarma);Regione Campania(PO-FESR 2014-2020,PO-FESR 2014-2020);Italian Ministry of Health(Piano Operativo Salute Traiettoria 3,‘Genomed’).supported by the Giovanni Armenise-Harvard Foundation,the Telethon Foundation(TCP13013);ERC(ERC Starting Grant,‘MetEpiStem’);supported by ERC(ERC Consolidator 615879);the Bill and Melinda Gates Foundation(OPP1035881 and OPP1097238);the Italian Foundation for Cancer Research(AIRC 21850);the Collaborative Center for XDP at Massachusetts General Hospital(239295);supported by the Italian Foundation for Cancer Research(AIRC-MFAG 25745);University of Padua(STARS Consolidator Grant,‘EMERALD’);supported by the Italian Foundation for Cancer Research(AIRC 2135);Italian Ministry of Health(RCR-201923669115,NET-201602361632);supported by the EVA-GLOBAL project that has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement number 871029;EVA-GLOBAL provided access to SARS-CoV-2 Alpha and Delta isolates(human nCoV19 isolate/England/MIG457/2020 and hCoV-19/Netherlands/NH-RIVM-27142/2021_P2).

摘　　要：The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants,some of which are resistant to vaccines and drugs targeting viral elements.Targeting host dependency factors,e.g.cellular proteins required for viral replication,would help prevent the development of resistance.However,it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host factors.To this end,we compared three variants of concern and found that the host transcriptional response was conserved,differing only in kinetics and magnitude.Clustered regularly interspaced short palindromic repeats screening identified host genes required for each variant during infection.Most of the genes were shared by multiple variants.We validated our hits with small molecules and repurposed the US Food and Drug Administration-approved drugs.All the drugs were highly active against all the tested variants,including new variants that emerged during the study(Delta and Omicron).Mechanistically,we identified reactive oxygen species production as a key step in early viral replication.Antioxidants such as N-acetyl cysteine(NAC)were effective against all the variants in both human lung cells and a humanized mouse model.Our study supports the use of available antioxidant drugs,such as NAC,as a general and effective anti-COVID-19 approach.

关 键 词：SARS-CoV-2 variants of concern host dependency factors antivirals N-acetyl cysteine 

分 类 号：R373[医药卫生—病原生物学]