The huge loss of life and major damage to the social fabric that is caused by a viral pandemic has been brought graphically to light with the current SARS-CoV-2 (COVID-19) crisis. Clearly, broad-spectrum antiviral agents that are effective therapeutically and prophylactically against SARS-CoV-2, anticipate other epidemic coronaviruses that emerge from animal reservoirs, and can be administered easily at home or in the outpatient clinic are much needed. Vaccines against SARS-CoV-2 have been remarkably effective, but waning immunity, viral evolution, distribution issues, and social resistance to vaccines have slowed progress. We have created a promising new broad-spectrum anti-coronavirus agent through molecular engineering of a high mannose-binding lectin from bananas, BanLec. The resulting lectin, termed H84T-BanLec (H84T), is the first in which two functions of a lectin have been separated by targeted engineering, leading to loss of mitogenicity (unwanted immune activation) and retention of broad-spectrum antiviral activity; H84T binds to the high mannose on viral envelopes and blocks attachment and fusion to the host cell. We have demonstrated the efficacy of H84T against influenza A and B, HIV, hepatitis C, and Ebola. In mouse (immunocompetent, immunodeficient, and with a humanized immune system), rat, and hamster studies, H84T is well-tolerated. (The selectivity for viruses is based on the fact that high mannose (as opposed to simple mannose) is not present on most healthy animal cells). We have now shown that H84T is effective in vitro against SARS-CoV-2 (including the Omicron variant), SARS-CoV-1, MERS-CoV, and all other coronaviruses tested (all have high mannose on their surface spike protein). H84T is also effective in vivo against MERS-CoV and SARS-CoV-2, the latter whether H84T is delivered systemically or intranasally or as prophylaxis or as therapy. Atomic force microscopy and other modalities reveal that H84T creates multiple, independent, tight bonds with high mannose residues on the spike protein, in keeping with the strong and broad-spectrum antiviral activity. We now propose to further study the mechanism of action and activity of H84T against SARS-CoV-2 variants and coronaviruses from animal reservoirs with pandemic potential. To yet further enhance the potency of H84T and improve large- scale production, we will create and test both molecularly-evolved H84T and H84T-antibody hybrid molecules (“lectibodies”). As the use of H84T as an intranasal agent is likely to be the route by which we can reach many more people, we will optimize formulations for the safe and sustained intranasal release of the molecule. We will further test the therapeutic and prophylactic activity of H84T and derivatives against SARS-CoV-2 variants and emerging coronaviruses in animal models. The development of H84T as an intranasal anti-SARS-CoV-2 drug and pan-coronavirus agent will allow us to provide treatment and/or prophylaxis in coronavirus (and influ...