Key result
LNA gapmers targeting SARS-CoV-2 s2m inhibit in vitro viral replication, reducing protein expression by ~93%.
Why the study?
The evolutionary conservation and presence of the stemloop 2 motif across viral subgenomic transcripts implicate a key role in the viral infection cycle of viruses including SARS-CoV-2.
Do LNA gapmers targeting the s2m element inhibit SARS-CoV-2 replication in vitro?
Do LNA gapmers targeting the s2m element inhibit SARS-CoV-2 replication in vitro?
Absolute Event Rate: 6.9% vs 100%
LNA gapmers targeting the highly conserved s2m element of SARS-CoV-2 effectively inhibit viral replication in vitro, presenting a potential antiviral therapeutic strategy.
Inhibits SARS-CoV-2 in cell culture; hypothesis-generating for s2m LNA gapmers, pending in vivo and clinical validation.
Summary RNA structural elements occur in numerous single stranded (+)-sense RNA viruses. The stemloop 2 motif (s2m) is one such element with an unusually high degree of sequence conservation, being found in the 3’ UTR in the genomes of many astroviruses, some picornaviruses and noroviruses, and a variety of coronaviruses, including SARS-CoV and SARS-CoV-2. The evolutionary conservation and its occurrence in all viral subgenomic transcripts implicates a key role of s2m in the viral infection cycle. Our findings indicate that the element, while stably folded, can nonetheless be invaded and remodelled spontaneously by antisense oligonucleotides (ASOs) that initiate pairing in exposed loops and trigger efficient sequence-specific RNA cleavage in reporter assays. ASOs also act to inhibit replication in an astrovirus replicon model system in a sequence-specific, dose-dependent manner and inhibit SARS-CoV-2 infection in cell culture. Our results thus permit us to suggest that the s2m element is a site of vulnerability readily targeted by ASOs, which show promise as anti-viral agents.
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Lulla et al. (2020) studied SARS-CoV-2 infection (preclinical models). LNA ASO gapmers targeting s2m vs. Scrambled gapmers or no treatment was evaluated on Inhibition of SARS-CoV-2 infection/replication in cell culture. LNA gapmers targeting the highly conserved s2m element of SARS-CoV-2 inhibited viral replication in cell culture, reducing N protein expression to as low as 6.9% of untreated controls at 1 µM.
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