An engineered peptide given to ferrets two days before they were co-housed with SARS-CoV-2-infected animals prevented virus transmission to the treated ferrets, a new study shows. The peptides used are highly stable and thus have the potential to translate into effective intranasal prophylaxis to reduce infection and severe SARS-CoV-2 disease in humans, the study's authors say. The SARS-CoV-2 spike (S) protein binds to host cells to initiate infection. This stage in the virus life history is a target for drug inhibition. Here, researchers with past success designing lipopeptide fusion inhibitors that block this critical first step of infection for SARS-CoV-2 and other viruses sought to design a SARS-CoV-2-specific inhibitor that was highly potent. Testing various designs in cell culture, Rory D. de Vries and colleagues identified one particularly effective lipopeptide against SARS-CoV-2, which also inhibited binding by emerging SARS-CoV-2 variants, including B.1.1.7 and B.1.351. In further studies of this candidate in the lungs of humanized mice, it persisted in the respiratory tract, a sign that it can protect against virus replication. To test the ability of their leading inhibitor candidate to block viral transmission, the researchers turned to ferrets, a model for evaluating airborne virus spread (although ferrets do not display strong clinical symptoms after infection). Some ferrets in the authors' study were dosed with the peptide before being co-housed with SARS-CoV-2-infected ferrets for 24 hours; other ferrets weren't. After this 24-hour period, SARS-CoV-2 was not detected in the throats or noses of any treated ferrets, while infectious virus was detected in all untreated ferrets. In further experiments with ferrets, the authors show that administration of the peptide intranasally just two hours before exposure delayed infection. They say their intranasal peptide offers "successful prophylaxis that prevents SARS-CoV-2 transmission in a relevant animal model" and "should readily translate into a safe and effective nasal spray or inhalation administered fusion inhibitor for SARS-CoV-2 prophylaxis." They also note that a combination of drugs that target different aspects of the viral life cycle would likely be best-suited for SARS-CoV-2.