Chemically Modified Bovine β-Lactoglobulin as a Broad-Spectrum Influenza Virus Entry Inhibitor with the Potential to Combat Influenza Outbreaks
Yuhong Fu,
Peiyu Li,
Wei Xu,
Zezhong Liu,
Cong Wang,
Qian Wang,
Jiayi Tang,
Weihua Li,
Lu Lu,
Shibo Jiang
Affiliations
Yuhong Fu
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China
Peiyu Li
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China
Wei Xu
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China
Zezhong Liu
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China
Cong Wang
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China
Qian Wang
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China
Jiayi Tang
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China
Weihua Li
NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, 2140 Xie Tu Rd., Xuhui District, Shanghai 200032, China
Lu Lu
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China
Shibo Jiang
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China
Frequent outbreaks of the highly pathogenic influenza A virus (AIV) infection, together with the lack of broad-spectrum influenza vaccines, call for the development of broad-spectrum prophylactic agents. Previously, 3-hydroxyphthalic anhydride-modified bovine β-lactoglobulin (3HP-β-LG) was proven to be effective against human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it has also been used in the clinical control of cervical human papillomavirus (HPV) infections. Here, we show its efficacy in potently inhibiting infection by divergent influenza A and B viruses. Mechanistic studies suggest that 3HP-β-LG binds, possibly through its negatively charged residues, to the receptor-binding domain in the hemagglutinin 1 (HA1) subunit in the HA of the influenza virus, thus inhibiting the attachment of the HA to sialic acid on host cells. The intranasal administration of 3HP-β-LG led to the protection of mice against challenges by influenza A(H1N1)/PR8, A(H3N2), and A(H7N9) viruses. Furthermore, 3HP-β-LG is highly stable when stored at 50 °C for 30 days and it shows excellent safety in vitro and in vivo. Collectively, our findings suggest that 3HP-β-LG could be successfully repurposed as an intranasal prophylactic agent to prevent influenza virus infections during influenza outbreaks.
