Targeting RNA Structure as a Therapeutic Strategy
Dr. Rouskin’s lab characterized the ensembles of secondary structures across the entire RNA genome of SARS-CoV-2 during infection of VeroE6 and Huh7 cells. They found that at least half of the genome forms alternative structures in cells. Of particular interest, was the frameshifting stimulation element (FSE), which causes a fraction of ribosomes to slip backward by 1 nt, bypass a stop codon in the middle of open reading frame 1 and translate five essential proteins, including the viral RNA polymerase. Numerous studies have shown that inhibiting ribosomal frameshifting impairs the replication of coronaviruses, including SARS-CoV-2. Surprisingly, they found that sequences flanking the FSE upregulate ribosomal frameshifting, and furthermore that one of the alternative structures of the FSE involves an RNA-RNA interaction with an element 1.2 kb downstream.
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