G-quadruplex-forming small RNA inhibits coronavirus and influenza A virus replication

Future pandemic threats may be caused by novel coronaviruses and influenza
A viruses. Here we show that when directly added to a cell culture,
guanosine 12mer (G12) and its phosphorothioate-linked derivatives
(G12(S)), rapidly entered cytoplasm and suppressed the propagation of
human coronaviruses and influenza A viruses to between 1/100 and nearly
1/1000 of normal virus infectivity without cellular toxicity and induction
of innate immunity. Moreover, G12(S) alleviated the weight loss caused by
coronavirus infection in mice. G12(S) might exhibit a stable G-tetrad with
left-handed parallel-stranded G-quadruplex, and inhibit the replication
process by impeding interaction between viral nucleoproteins and viral RNA
in the cytoplasm. Unlike previous antiviral strategies that target the
G-quadruplexes of the viral genome, we now show that excess exogenous
G-quadruplex-forming small RNA displaces genomic RNA from
ribonucleoprotein, effectively inhibiting viral replication. The approach
has the potential to facilitate the creation of versatile middle-molecule
antivirals featuring lipid nanoparticle-free delivery.