Article ; Online: Cryo-EM and antisense targeting of the 28-kDa frameshift stimulation element from the SARS-CoV-2 RNA genome.
Nature structural & molecular biology
2021 Volume 28, Issue 9, Page(s) 747–754
Abstract: Drug discovery campaigns against COVID-19 are beginning to target the SARS-CoV-2 RNA genome ... is a particularly attractive SARS-CoV-2 RNA target. Here we present a 6.9 Å resolution cryo-EM ... that impair FSE function in frameshifting assays and knock down SARS-CoV-2 virus replication in A549-ACE2 ...
| Abstract | 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. |
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| MeSH term(s) | A549 Cells ; Animals ; Base Sequence ; COVID-19/prevention & control ; COVID-19/virology ; Cell Line, Tumor ; Chlorocebus aethiops ; Cryoelectron Microscopy/methods ; Frameshift Mutation/genetics ; Genome, Viral/genetics ; Humans ; Models, Molecular ; Nucleic Acid Conformation ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/pharmacology ; RNA, Viral/chemistry ; RNA, Viral/genetics ; RNA, Viral/ultrastructure ; Response Elements/genetics ; SARS-CoV-2/genetics ; SARS-CoV-2/physiology ; SARS-CoV-2/ultrastructure ; Vero Cells ; Virus Replication/drug effects ; Virus Replication/genetics |
| Chemical Substances | Oligonucleotides, Antisense ; RNA, Viral |
| Language | English |
| Publishing date | 2021-08-23 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S. |
| ZDB-ID | 2126708-X |
| ISSN | 1545-9985 ; 1545-9993 |
| ISSN (online) | 1545-9985 |
| ISSN | 1545-9993 |
| DOI | 10.1038/s41594-021-00653-y |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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