Genome-wide mapping of SARS-CoV-2 RNA structures identifies therapeutically-relevant elements.
5' Untranslated Regions
/ genetics
Algorithms
Antiviral Agents
/ chemistry
Base Sequence
Binding Sites
/ genetics
COVID-19
/ epidemiology
Conserved Sequence
/ genetics
Genome, Viral
/ genetics
Humans
Models, Molecular
Nucleic Acid Conformation
Pandemics
RNA, Viral
/ chemistry
SARS-CoV-2
/ drug effects
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
16 12 2020
16 12 2020
Historique:
accepted:
22
10
2020
revised:
13
10
2020
received:
13
09
2020
pubmed:
10
11
2020
medline:
29
12
2020
entrez:
9
11
2020
Statut:
ppublish
Résumé
SARS-CoV-2 is a betacoronavirus with a linear single-stranded, positive-sense RNA genome, whose outbreak caused the ongoing COVID-19 pandemic. The ability of coronaviruses to rapidly evolve, adapt, and cross species barriers makes the development of effective and durable therapeutic strategies a challenging and urgent need. As for other RNA viruses, genomic RNA structures are expected to play crucial roles in several steps of the coronavirus replication cycle. Despite this, only a handful of functionally-conserved coronavirus structural RNA elements have been identified to date. Here, we performed RNA structure probing to obtain single-base resolution secondary structure maps of the full SARS-CoV-2 coronavirus genome both in vitro and in living infected cells. Probing data recapitulate the previously described coronavirus RNA elements (5' UTR and s2m), and reveal new structures. Of these, ∼10.2% show significant covariation among SARS-CoV-2 and other coronaviruses, hinting at their functionally-conserved role. Secondary structure-restrained 3D modeling of these segments further allowed for the identification of putative druggable pockets. In addition, we identify a set of single-stranded segments in vivo, showing high sequence conservation, suitable for the development of antisense oligonucleotide therapeutics. Collectively, our work lays the foundation for the development of innovative RNA-targeted therapeutic strategies to fight SARS-related infections.
Identifiants
pubmed: 33166999
pii: 5961787
doi: 10.1093/nar/gkaa1053
pmc: PMC7736786
doi:
Substances chimiques
5' Untranslated Regions
0
Antiviral Agents
0
RNA, Viral
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12436-12452Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Nucleic Acids Res. 2012 Jan;40(Database issue):D593-8
pubmed: 22006842
J Virol. 2004 Jan;78(2):669-82
pubmed: 14694098
Nucleic Acids Res. 2020 Jul 2;48(W1):W292-W299
pubmed: 32504492
Nat Struct Mol Biol. 2021 Sep;28(9):747-754
pubmed: 34426697
Nat Methods. 2018 Oct;15(10):785-788
pubmed: 30202058
Bioorg Med Chem. 2019 Jun 1;27(11):2253-2260
pubmed: 30982658
Bioinformatics. 2013 Nov 15;29(22):2933-5
pubmed: 24008419
Virol J. 2013 Apr 25;10:132
pubmed: 23618040
Nature. 2020 Mar;579(7798):270-273
pubmed: 32015507
Nat Struct Mol Biol. 2018 Aug;25(8):677-686
pubmed: 30061596
RNA. 2011 Sep;17(9):1747-59
pubmed: 21799029
PLoS Pathog. 2013;9(7):e1003500
pubmed: 23874204
Algorithms Mol Biol. 2011 Nov 24;6:26
pubmed: 22115189
Nat Rev Drug Discov. 2018 Aug;17(8):547-558
pubmed: 29977051
Mol Biol Evol. 2013 Apr;30(4):772-80
pubmed: 23329690
Virus Evol. 2016 Jun 10;2(1):vew014
pubmed: 28694997
Methods Mol Biol. 2020;2165:103-125
pubmed: 32621221
Antiviral Res. 2008 Apr;78(1):26-36
pubmed: 18258313
BMC Bioinformatics. 2009 Jun 02;10:168
pubmed: 19486540
Antimicrob Agents Chemother. 2011 Jul;55(7):3105-14
pubmed: 21502629
Nucleic Acids Res. 2016 Apr 20;44(7):e63
pubmed: 26687716
Nat Methods. 2014 Sep;11(9):959-65
pubmed: 25028896
Mol Cell. 2016 May 19;62(4):603-17
pubmed: 27184079
Nucleic Acids Res. 2018 Sep 19;46(16):e97
pubmed: 29893890
Cell. 1989 May 19;57(4):537-47
pubmed: 2720781
Nat Commun. 2016 Jun 24;7:12023
pubmed: 27338251
Nature. 2015 Mar 26;519(7544):486-90
pubmed: 25799993
J Gen Virol. 1998 Apr;79 ( Pt 4):715-8
pubmed: 9568965
Annu Rev Virol. 2019 Sep 29;6(1):93-117
pubmed: 31337286
Virus Res. 2015 Aug 3;206:120-33
pubmed: 25736566
Nucleic Acids Res. 2019 Jul 26;47(13):7003-7017
pubmed: 31053845
Nucleic Acid Ther. 2016 Oct;26(5):277-285
pubmed: 27463680
Nature. 2014 Jan 30;505(7485):701-5
pubmed: 24336214
Nucleic Acids Res. 2012 Aug;40(15):e115
pubmed: 22730293
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Annu Rev Med. 2019 Jan 27;70:307-321
pubmed: 30691367
RNA. 2020 Aug;26(8):937-959
pubmed: 32398273
J Virol. 2007 Feb;81(3):1274-87
pubmed: 17093194
Nat Rev Microbiol. 2016 Aug;14(8):523-34
pubmed: 27344959
Adv Virus Res. 2016;96:127-163
pubmed: 27712622
Nat Methods. 2017 Jan;14(1):45-48
pubmed: 27819659
Nat Rev Microbiol. 2019 Mar;17(3):181-192
pubmed: 30531947
Nat Chem Biol. 2013 Jan;9(1):18-20
pubmed: 23178934
BMC Struct Biol. 2019 Mar 21;19(1):5
pubmed: 30898165
Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):97-102
pubmed: 19109441
Nat Commun. 2019 Mar 29;10(1):1408
pubmed: 30926818
Nucleic Acids Res. 2014 Oct 29;42(19):e151
pubmed: 25159614
Mol Cell. 2020 Dec 17;80(6):1067-1077.e5
pubmed: 33259809
Mol Ther Nucleic Acids. 2019 Sep 6;17:615-625
pubmed: 31394430
Nucleic Acids Res. 2016 Jul 8;44(W1):W315-9
pubmed: 27095203
J Virol. 2010 Oct;84(19):9733-48
pubmed: 20660197
Virology. 2018 Apr;517:44-55
pubmed: 29223446
BMC Bioinformatics. 2002;3:2
pubmed: 11869452
Nucleic Acids Res. 2017 Sep 19;45(16):9716-9725
pubmed: 28934475
J Am Chem Soc. 2011 Jul 6;133(26):10094-100
pubmed: 21591761
Cell. 2016 May 19;165(5):1267-1279
pubmed: 27180905
PLoS Biol. 2005 Jan;3(1):e5
pubmed: 15630477
Nat Methods. 2017 Jan;14(1):75-82
pubmed: 27819661
Wiley Interdiscip Rev RNA. 2016 Nov;7(6):726-743
pubmed: 27307213