Summary 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 Using icSHAPE, we determined the structural landscape of SARS-CoV-2 RNA in infected human cells and from refolded RNAs, as well as of 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