Antisense oligonucleotides target a nearly invariant structural element from the SARS CoV 2 genome and drive RNA degradation
The SARS CoV 2 virus contains an unusually large, single stranded RNA genome that is punctuated with structured elements of unknown function, such as the s2m element located in the 3 untranslated region. The evolutionary conservation of the s2m element and its occurrence in all viral subgenomic transcripts implicates a key role in the viral infection cycle. In order to exploit this element as a potential therapeutic target, we have designed antisense "gapmer" oligonucleotides that efficiently base pair to the s2m region. These oligonucleotides, composed of locked nucleic acids (LNA) flanking a central DNA core, successfully remodel the s2m structure and induce sequence specific RNA cleavage by RNase H in vitro. Gapmers are also effective in human cells as they reduce the fluorescence signal in GFP reporter assays and cause a dose dependent reduction in replication in a model replicon system based on a human astrovirus. Overall, these oligonucleotides show promise as anti viral agents and may serve as a helpful starting point to develop treatments for COVID 19.