Abstract
“Pan-coronavirus” antivirals targeting conserved viral components can be designed. Here, we show that the rationally engineered H84T-banana lectin (H84T-BanLec), which specifically recognizes high mannose found on viral proteins but seldom on healthy human cells, potently inhibits Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (including Omicron), and other human-pathogenic coronaviruses at nanomolar concentrations. H84T-BanLec protects against MERS-CoV and SARS-CoV-2 infection in vivo. Importantly, intranasally and intraperitoneally administered H84T-BanLec are comparably effective. Mechanistic assays show that H84T-BanLec targets virus entry. High-speed atomic force microscopy depicts real-time multimolecular associations of H84T-BanLec dimers with the SARS-CoV-2 spike trimer. Single-molecule force spectroscopy demonstrates binding of H84T-BanLec to multiple SARS-CoV-2 spike mannose sites with high affinity and that H84T-BanLec competes with SARS-CoV-2 spike for binding to cellular ACE2. Modeling experiments identify distinct high-mannose glycans in spike recognized by H84T-BanLec. The multiple H84T-BanLec binding sites on spike likely account for the drug compound’s broad-spectrum antiviral activity and the lack of resistant mutants.
Keywords: MERS-CoV; SARS-CoV-2; antiviral; atomic force microscopy; banana; coronavirus; lectin; single-molecule force spectroscopy; spike; treatment.
【저자키워드】 SARS-CoV-2, coronavirus, Antiviral, spike, MERS-CoV, Treatment., Atomic force microscopy, lectin, banana, single-molecule force spectroscopy, 【초록키워드】 Treatment, ACE2, SARS-COV-2 infection, antiviral activity, omicron, binding site, Microscopy, modeling, virus entry, target, experiment, in vivo, glycan, binding, SARS-CoV-2 spike, association, cellular, Middle East, acute respiratory syndrome, Viral protein, human cells, high affinity, resistant mutants, respiratory syndrome coronavirus, component, spike trimer, Administered, effective, concentrations, PROTECT, identify, lack, conserved, healthy, intranasally, inhibit, coronavirus, atomic, recognize, high-mannose, intraperitoneally, the SARS-CoV-2, 【제목키워드】 in vivo, MERS-CoV infection, inhibit,