In vivo structural characterization of the SARS-CoV-2 RNA genome identifies host proteins vulnerable to repurposed drugs

• Published in: Cell Vol. 184; no. 7; pp. 1865 - 1883.e20
• Main Authors: Sun, Lei, Li, Pan, Ju, Xiaohui, Rao, Jian, Huang, Wenze, Ren, Lili, Zhang, Shaojun, Xiong, Tuanlin, Xu, Kui, Zhou, Xiaolin, Gong, Mingli, Miska, Eric, Ding, Qiang, Wang, Jianwei, Zhang, Qiangfeng Cliff
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021
• Subjects: Animals; Cell Line; Chlorocebus aethiops; computer simulation; COVID-19 Drug Treatment; COVID-19 infection; Deep Learning; Drug Repositioning; drug reproposing; genome; host factor; Humans; landscapes; liver; lungs; Nucleic Acid Conformation; oligonucleotides; pandemic; RBP binding prediction; RNA; RNA secondary structure; RNA, Viral - chemistry; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - metabolism; SARS-CoV-2; SARS-CoV-2 - drug effects; SARS-CoV-2 - genetics; Severe acute respiratory syndrome coronavirus 2; therapeutics; SARS-CoV-2; host factor; RBP binding prediction; drug reproposing; RNA secondary structure
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2021.02.008

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding of the RNA virus and its interactions with host proteins could improve therapeutic interventions for COVID-19. By using icSHAPE, we determined the structural landscape of SARS-CoV-2 RNA in infected human cells and from refolded RNAs, as well as the regulatory untranslated regions of SARS-CoV-2 and six other coronaviruses. We validated several structural elements predicted in silico and discovered structural features that affect the translation and abundance of subgenomic viral RNAs in cells. The structural data informed a deep-learning tool to predict 42 host proteins that bind to SARS-CoV-2 RNA. Strikingly, antisense oligonucleotides targeting the structural elements and FDA-approved drugs inhibiting the SARS-CoV-2 RNA binding proteins dramatically reduced SARS-CoV-2 infection in cells derived from human liver and lung tumors. Our findings thus shed light on coronavirus and reveal multiple candidate therapeutics for COVID-19 treatment. [Display omitted] •We generated in vivo structure maps and models of the SARS-CoV-2 RNA genome•Comparative analysis discovered conserved RNA structural features across coronaviruses•RNA structure-based prediction identified host proteins binding the SARS-CoV-2 genome•FDA-approved drugs targeting predicted host proteins potently suppress viral infection Sun et al. determined the SARS-CoV-2 RNA genome structure in infected cells and from refolded RNAs, which enabled prediction of 42 host proteins that bind to viral RNA, using a deep-learning tool and identification of FDA-approved drugs for repurposing to reduce SARS-CoV-2 infection in cells.