Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused a pandemic worldwide.Currently,however,no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019(COVID-19).Here,we report our discovery of a promising anti-COVID-19 drug candidate,the lipoglycopeptide antibiotic dalbavancin,based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays.Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2(ACE2)with high affinity,thereby blocking its interaction with the SARS-CoV-2 spike protein.Furthermore,dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of～12nM.In both mouse and rhesus macaque models,viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration.Given its high safety and long plasma half-life(8-10 days)shown in previous clinical trials,our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.