Mucin anchoring of SARS-CoV-2 neutralizing nanobinders increases intranasal antiviral efficacy

Abstract Respiratory viruses represent a major threat for human health, and despite effectiveness to limit the severity of the disease, they fail to block transmission. Recent advances have shown that the nasal cavity is the primal infection site of respiratory viruses, and thus represents a very attractive target for prophylactic treatment with antivirals in order to limit virus dissemination. However, mucociliary clearance limits the efficiency of a local treatment in the nasal cavity. We have previously developed a potent anti-Spike nanobinder blocking SARS-CoV-2 entry. Here, it was used as a proof of concept to show the strength of anchoring this synthetic antiviral to the mucin layer with a mucin-binding domain, increasing its residence time in the nasal cavity up to 6 hours post-instillation. This was very effective as a prophylactic treatment to limit infection of sentinel hamsters. Our strategy could be extended to antivirals against other major respiratory viruses such as RSV or influenza viruses, but also in other diseases by targeting specific epithelia increasing residence time and local concentration of the drug.