Abstract Brilacidin, a mimetic of host defense peptides (HDPs), is currently in Phase 2 clinical trial as an antibiotic drug candidate. A recent study reported that brilacidin has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by inactivating the virus. In this study, we discovered an additional mechanism of action of brilacidin by targeting heparan sulfate proteoglycans (HSPGs) on the host cell surface. Brilacidin, but not acetyl brilacidin, inhibits the entry of SARS‐CoV‐2 pseudovirus into multiple cell lines, and heparin, an HSPG mimetic, abolishes the inhibitory activity of brilacidin on SARS‐CoV‐2 pseudovirus cell entry. In addition, we found that brilacidin has broad‐spectrum antiviral activity against multiple human coronaviruses (HCoVs) including HCoV‐229E, HCoV‐OC43, and HCoV‐NL63. Mechanistic studies revealed that brilacidin has a dual antiviral mechanism of action including virucidal activity and binding to coronavirus attachment factor HSPGs on the host cell surface. Brilacidin partially loses its antiviral activity when heparin was included in the cell cultures, supporting the host‐targeting mechanism. Drug combination therapy showed that brilacidin has a strong synergistic effect with remdesivir against HCoV‐OC43 in cell culture. Taken together, this study provides appealing findings for the translational potential of brilacidin as a broad‐spectrum antiviral for coronaviruses including SARS‐CoV‐2. Highlights Brilacidin has broad‐spectrum antiviral activity against multiple human coronaviruses (HCoVs) including HCoV‐229E, HCoV‐OC43, and HCoV‐NL63 Brilacidin, but not acetyl brilacidin, inhibits the entry of SARS‐CoV‐2 pseudovirus into multiple cell lines Heparin, an heparan sulfate proteoglycans (HSPG) mimetic, abolishes the inhibitory activity of brilacidin on SARS‐CoV‐2 pseudovirus cell entry Brilacidin has a dual antiviral mechanism of action including virucidal activity and binding to coronavirus attachment factor HSPGs on the host cell surface.
【저자키워드】 COVID19, Antiviral, SARS‐CoV‐2, brilacidin, HSPGs, human coronavirus, 【초록키워드】 coronavirus, clinical trial, Phase 2, peptide, Remdesivir, combination therapy, drug, antiviral activity, heparin, virus, SARS‐CoV‐2, pseudovirus, Cell culture, virucidal, mechanism of action, mechanism, binding, antibiotic, acute respiratory syndrome, cell entry, inhibitory activity, drug candidate, cell cultures, Defense, multiple cell lines, Host, synergistic, host cell surface, human coronavirus, reported, addition, inhibit, provide, translational, Proteoglycan, multiple cell line, 【제목키워드】 antiviral activity, virus, COVID‐19, NL63, OC43, 229E, host cell, drug candidate, human coronavirus,