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. 2025 May 11;28(6):112632.
doi: 10.1016/j.isci.2025.112632. eCollection 2025 Jun 20. Targeting G9a-m6A translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae
Adil Muneer 1 , Ling Xie 1 , Xuping Xie 2 3 , Feng Zhang 4 , John A Wrobel 1 , Yan Xiong 5 , Xufen Yu 5 , Charles Wang 6 , Ciprian Gheorghe 6 , Ping Wu 7 , Juan Song 8 , Guo-Li Ming 4 , Jian Jin 5 , Hongjun Song 4 , Pei-Yong Shi 2 7 3 , Xian Chen 1 9
Affiliations
N6-methyladenosine (m6A) modification pathway is hijacked by several RNA viruses, including SARS-CoV-2, making it an attractive host-directed target for development of broad-spectrum antivirals. Here, we show that histone methyltransferase G9a, through its interaction with METTL3, regulates SARS-CoV-2-mediated rewiring of host m6A methylome to ultimately promote turnover, abundance, secretion and/or phosphorylation of various viral receptors and proteases, transcription factors, cytokines/chemokines, coagulation and angiogenesis associated proteins, and fibrosis markers. More importantly, drugs targeting G9a and its associated protein EZH2 are potent inhibitors of SARS-CoV-2 replication and reverse multi-omic effects of coronavirus infection in human alveolar epithelial cells (A549-hACE2) and COVID-19 patient peripheral blood mononuclear cells (PBMCs)-with similar changes seen in multiorgan autopsy samples from COVID-19 patients. Altogether, we extend G9a function(s) beyond transcription to translational regulation during COVID-19 pathogenesis and show that targeting this master regulatory complex represents a new strategy (drug-class) that can be leveraged to combat emerging anti-viral resistance and infections.
Keywords: Biological sciences; Microbiology; Natural sciences; Virology.
. 2025 May 11;28(6):112632.
doi: 10.1016/j.isci.2025.112632. eCollection 2025 Jun 20. Targeting G9a-m6A translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae
Adil Muneer 1 , Ling Xie 1 , Xuping Xie 2 3 , Feng Zhang 4 , John A Wrobel 1 , Yan Xiong 5 , Xufen Yu 5 , Charles Wang 6 , Ciprian Gheorghe 6 , Ping Wu 7 , Juan Song 8 , Guo-Li Ming 4 , Jian Jin 5 , Hongjun Song 4 , Pei-Yong Shi 2 7 3 , Xian Chen 1 9
Affiliations
- PMID: 40510117
- PMCID: PMC12159498
- DOI: 10.1016/j.isci.2025.112632
N6-methyladenosine (m6A) modification pathway is hijacked by several RNA viruses, including SARS-CoV-2, making it an attractive host-directed target for development of broad-spectrum antivirals. Here, we show that histone methyltransferase G9a, through its interaction with METTL3, regulates SARS-CoV-2-mediated rewiring of host m6A methylome to ultimately promote turnover, abundance, secretion and/or phosphorylation of various viral receptors and proteases, transcription factors, cytokines/chemokines, coagulation and angiogenesis associated proteins, and fibrosis markers. More importantly, drugs targeting G9a and its associated protein EZH2 are potent inhibitors of SARS-CoV-2 replication and reverse multi-omic effects of coronavirus infection in human alveolar epithelial cells (A549-hACE2) and COVID-19 patient peripheral blood mononuclear cells (PBMCs)-with similar changes seen in multiorgan autopsy samples from COVID-19 patients. Altogether, we extend G9a function(s) beyond transcription to translational regulation during COVID-19 pathogenesis and show that targeting this master regulatory complex represents a new strategy (drug-class) that can be leveraged to combat emerging anti-viral resistance and infections.
Keywords: Biological sciences; Microbiology; Natural sciences; Virology.