Journal
BIOPHYSICAL JOURNAL
Volume 120, Issue 6, Pages 1040-1053Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2020.10.012
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Funding
- National Science Foundation RAPID Award from the Division of Mathematical Science [2030377]
- Division of Chemistry, National Institutes of Health from the National Institute of General Medical Sciences [R35GM122562]
- Philip Morris International
- Division Of Mathematical Sciences
- Direct For Mathematical & Physical Scien [2030377] Funding Source: National Science Foundation
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With the rapid spread of COVID-19, it is crucial to focus on the RNA of the virus, particularly on ribosomal frameshifting and pseudoknots, as potential targets for antiviral drugs and gene editing approaches.
With the rapid rate of COVID-19 infections and deaths, treatments and cures besides hand washing, social distancing, masks, isolation, and quarantines are urgently needed. The treatments and vaccines rely on the basic biophysics of the complex viral apparatus. Although proteins are serving as main drug and vaccine targets, therapeutic approaches targeting the 30,000 nucleotide RNA viral genome form important complementary approaches. Indeed, the high conservation of the viral genome, its close evolutionary relationship to other viruses, and the rise of gene editing and RNA-based vaccines all argue for a focus on the RNA agent itself. One of the key steps in the viral replication cycle inside host cells is the ribosomal frameshifting required for translation of overlapping open reading frames. The RNA frameshifting element (FSE), one of three highly conserved regions of coronaviruses, is believed to include a pseudoknot considered essential for this ribosomal switching. In this work, we apply our graph-theory-based framework for representing RNA secondary structures, RAG (or RNA-As-Graphs),'' to alter key structural features of the FSE of the SARS-CoV-2 virus. Specifically, using RAG machinery of genetic algorithms for inverse folding adapted for RNA structures with pseudoknots, we computationally predict minimal mutations that destroy a structurally important stem and/or the pseudoknot of the FSE, potentially dismantling the virus against translation of the polyproteins. Our microsecond molecular dynamics simulations of mutant structures indicate relatively stable secondary structures. These findings not only advance our computational design of RNAs containing pseudoknots, they pinpoint key residues of the SARS-CoV-2 virus as targets for antiviral drugs and gene editing approaches.
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