Our previous studies have demonstrated that the peptide-based pan-CoV fusion inhibitor EK1 and EK1C4 potently inhibit infection of divergent HCoVs by targeting their HR1 regions.9,20 In this study, we showed that EK1 peptides effectively blocked infection by pseudotyped SARS-CoV-2 variants B.1.1.7 and B.1.1.248 and the PsVs carrying single or multiple crucial mutations, such as N501Y, E484K, and N417N, in S proteins of the currently dominant variants. The gene discussed is PROS1; the disease is infection.