Reviving chloroquine for anti-SARS-CoV-2 treatment with cucurbit[7]uril-based supramolecular formulation

The wide-spreading SARS-CoV-2 virus has put the world into boiling water for more than a year,however pharmacological therapies to act effectively against coronavirus disease 2019(COVID-19)remain elusive.Chloroquine(CQ),an antimalarial drug,was found to exhibit promising antiviral activity in vitro and in vivo at a high dosage,thus CQ was approved by the FDA for the emergency use authorization(EUA)in the fight against COVID-19 in the US,but later was revoked the EUA status due to the severe clinical toxicity.Herein,we show that supramolecular formulation of CQ by a macrocyclic host,curcurbit[7]uril(CB[7]),reduced its non-specific toxicity and improved its antiviral activity against coronavirus,working in synergy with CB[7].CB[7]was found to form 1:1 host-guest complexes with CQ,with a binding constant of$104 L/mol.The CQ-CB[7]formulation decreased the cytotoxicity of CQ against Vero E6 and L-02 cell lines.In particular,the cytotoxicity of CQ(60 mmol/L)against both Vero E6 cell line and L-02 cell lines was completely inhibited in the presence of 300 mmol/L and 600 mmol/L CB[7],respectively.Furthermore,the CB[7]alone showed astonishing antiviral activity in SARS-CoV-2 infected Vero E6 cells and mouse hepatitis virus strain A59(MHV-A59)infected N2 A cells,and synergistically improved the antiviral activity of CQ-CB[7],suggesting that CB[7]-based CQ formulation has a great potential as a safe and effective antiviral agent against SARS-CoV-2 and other coronavirus.