Author: Zhang, Kaiming; Zheludev, Ivan N; Hagey, Rachel J; Haslecker, Raphael; Hou, Yixuan J; Kretsch, Rachael; Pintilie, Grigore D; Rangan, Ramya; Kladwang, Wipapat; Li, Shanshan; Wu, Marie Teng-Pei; Pham, Edward A; Bernardin-Souibgui, Claire; Baric, Ralph S; Sheahan, Timothy P; D'Souza, Victoria; Glenn, Jeffrey S; Chiu, Wah; Das, Rhiju
Title: Cryo-EM and antisense targeting of the 28-kDa frameshift stimulation element from the SARS-CoV-2 RNA genome Cord-id: jkmqwlw3 Document date: 2021_1_1
ID: jkmqwlw3
Snippet: 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 Ã… 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 thro
Document: 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 Ã… 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.
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