A G-quadruplex structure in the SARS-CoV-2 RNA recruits human topoisomerase I

The COVID-19 pandemic has led to millions of deaths. Although the pandemic state has been declared to have ended and the disease has become endemic, the number of circulating SARS-CoV-2 variants and the lack of decreasing trends around the world highlight the challenge the virus still poses. The viral RNA genome contains several structural elements including G-quadruplexes. These structures may facilitate the binding between an RNA and RNA-binding proteins. Herein, we investigated host cell proteins that get trapped by a G-quadruplex structure of the SARS-CoV-2 RNA. The identified proteins include the human DNA topoisomerase 1 (TOP1). The protein is known to interact with G-quadruplex-DNA, but here, we show an interaction with a G-quadruplex structure formed by the RNA of SARS-CoV-2, which has not been reported before. TOP1 may be recruited by the non-canonical secondary structure to resolve it, which may enhance viral replication. Interestingly, previous studies showed that TOP1 inhibition can suppress SARS-CoV-2-induced inflammation. Thus, after discovery of TOP1 as a binding partner of the SARS-CoV-2 G-quadruplex structure, we tested different compounds for their effect on the recruitment of TOP1 to the G-quadruplex. Notably, our data suggest that the known alkaloid berberine can stabilize the TOP1-G4-RNA-complex. Functionally, TOP1 is possibly recruited by the G-quadruplex to resolve this secondary structure, thereby enhancing viral replication. Thus, berberine is a promising lead compound that may inhibit viral replication.