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Cryo-EM and antisense targeting of the 28-kDa frameshift stimulation element from the SARS-CoV-2 RNA genome

2021; Nature Portfolio; Volume: 28; Issue: 9 Linguagem: Inglês

10.1038/s41594-021-00653-y

1545-9993

Kaiming Zhang, Ivan N. Zheludev, Rachel J. Hagey, Raphael Haslecker, Yixuan J. Hou, Rachael C. Kretsch, Grigore Pintilie, Ramya Rangan, Wipapat Kladwang, Shanshan Li, Marie Teng-Pei Wu, Edward A. Pham, Claire Bernardin-Souibgui, Ralph S. Baric, Timothy P. Sheahan, Victoria D’Souza, Jeffrey S. Glenn, Wah Chiu, Rhiju Das,

RNA and protein synthesis mechanisms

Drug discovery campaigns against COVID-19 are beginning to target the SARS-CoV-2 RNA genome. The highly conserved frameshift stimulation element (FSE), required for balanced expression of viral proteins, is a particularly attractive SARS-CoV-2 RNA target. Here we present a 6.9 Å resolution cryo-EM structure of the FSE (88 nucleotides, ~28 kDa), validated through an RNA nanostructure tagging method. The tertiary structure presents a topologically complex fold in which the 5' end is threaded through a ring formed inside a three-stem pseudoknot. Guided by this structure, we develop antisense oligonucleotides that impair FSE function in frameshifting assays and knock down SARS-CoV-2 virus replication in A549-ACE2 cells at 100 nM concentration.