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Principal Investigator: David Michael Markovitz
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2023
Award: $728,193
Funding agency: National Institute of Allergy and Infectious Diseases
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 influenza)
epidemics using an agent easily administered in the outpatient clinic and even at home so it can reach large
numbers of people.
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