Theoretical basis for stabilizing messenger RNA through secondary structure design.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
11 10 2021
11 10 2021
Historique:
accepted:
27
08
2021
revised:
17
08
2021
received:
10
03
2021
pubmed:
15
9
2021
medline:
21
10
2021
entrez:
14
9
2021
Statut:
ppublish
Résumé
RNA hydrolysis presents problems in manufacturing, long-term storage, world-wide delivery and in vivo stability of messenger RNA (mRNA)-based vaccines and therapeutics. A largely unexplored strategy to reduce mRNA hydrolysis is to redesign RNAs to form double-stranded regions, which are protected from in-line cleavage and enzymatic degradation, while coding for the same proteins. The amount of stabilization that this strategy can deliver and the most effective algorithmic approach to achieve stabilization remain poorly understood. Here, we present simple calculations for estimating RNA stability against hydrolysis, and a model that links the average unpaired probability of an mRNA, or AUP, to its overall hydrolysis rate. To characterize the stabilization achievable through structure design, we compare AUP optimization by conventional mRNA design methods to results from more computationally sophisticated algorithms and crowdsourcing through the OpenVaccine challenge on the Eterna platform. We find that rational design on Eterna and the more sophisticated algorithms lead to constructs with low AUP, which we term 'superfolder' mRNAs. These designs exhibit a wide diversity of sequence and structure features that may be desirable for translation, biophysical size, and immunogenicity. Furthermore, their folding is robust to temperature, computer modeling method, choice of flanking untranslated regions, and changes in target protein sequence, as illustrated by rapid redesign of superfolder mRNAs for B.1.351, P.1 and B.1.1.7 variants of the prefusion-stabilized SARS-CoV-2 spike protein. Increases in in vitro mRNA half-life by at least two-fold appear immediately achievable.
Identifiants
pubmed: 34520542
pii: 6370252
doi: 10.1093/nar/gkab764
pmc: PMC8499941
doi:
Substances chimiques
RNA, Double-Stranded
0
RNA, Messenger
0
RNA, Viral
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10604-10617Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM122579
Pays : United States
Commentaires et corrections
Type : UpdateOf
Type : ErratumIn
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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