Screening of metallohelices for enantioselective targeting SARS-CoV-2 RNA G-quadruplex

The emergence of numerous variants of SARS-CoV-2 still presents the major challenges in the fight against this disease by reducing the efficacy of vaccines and drugs. RNA G-quadruplexes (G4s) in the SARS-CoV-2 genome are highly conserved and have thus been spotlighted as a promising therapeutic target to combat a wider range of variants. However, very few RNA G4 specific compounds have been reported. Here, a small library of 64 chiral metallohelices has been constructed for screening SARS-CoV-2 G4-specific binders. After screening, we found that one pair of the enantiomers showed the best enantioselectivity. The Λ enantiomer can strongly stabilize SARS-CoV-2 G4s, inhibit the expression of virus protein, and reduce the SARS-CoV-2 RNA copies and viral titers in Vero E6 cells. In contrast, the Δ enantiomer has much weaker effects than the Λ enantiomer under the same experimental conditions, showing an obvious enantioselectivity. Further studies indicate that the Λ enantiomer prefers binding to SARS-CoV-2 G4s rather than binding to the single/double-stranded DNA and commonly reported human DNA G4s, indicating its selectivity to RNA G4s. This work provides the first example for enantioselectively targeting SARS-CoV-2 G4s, and will promote developing drug candidates for targeting virus G4s.