Discovery of N-Containing (-)-Borneol Esters as Respiratory Syncytial Virus Fusion Inhibitors

Respiratory syncytial virus (RSV) causes acute respiratory infections, thus, posing a serious threat to the health of infants, children, and elderly people. In this study, we have discovered a series of potent RSV entry inhibitors with the (-)-borneol scaffold. The active compounds 3b, 5a, 5c, 7b, 9c, 10b, 10c, and 14b were found to exhibit activity against RSV A strain A2 in HEp-2 cells. The most active substances, 3b (IC50 = 8.9 mu M, SI = 111) and 5a (IC50 = 5.0 mu M, SI = 83), displayed more potency than the known antiviral agent Ribavirin (IC50 = 80.0 mu M, SI = 50). Time-of-addition assay and temperature shift studies demonstrated that compounds 3b, 5a, and 6b inhibited RSV entry, probably by interacting with the viral F protein that mediated membrane fusion, while they neither bound to G protein nor inhibited RSV attachment to the target cells. Appling procedures of molecular modeling and molecular dynamics, the binding mode of compounds 3b and 5a was proposed. Taken together, the results of this study suggest (-)-borneol esters to be promising lead compounds for developing new anti-RSV agents.

Automated summary

In this study, a series of potent respiratory syncytial virus (RSV) entry inhibitors with the (-)-borneol scaffold were discovered. The most active compounds, 3b and 5a, showed higher potency than the known antiviral agent Ribavirin. Time-of-addition and temperature shift studies suggested that these compounds inhibit RSV entry by interacting with the viral F protein. Molecular modeling and dynamics confirmed the binding mode of compounds 3b and 5a. These findings highlight the potential of (-)-borneol esters as lead compounds for developing new anti-RSV agents.