Punicalin targets RSV glycoprotein and fusion protein at non-overlapping sites to prevent viral escape.
TL;DR
In RSV-infected mice, nebulized PUN provides sustained respiratory exposure, reduces lung viral loads and pathology, and attenuates inflammatory responses, and in RSV-infected mice, nebulized PUN provides sustained respiratory exposure, reduces lung viral loads and pathology, and attenuates inflammatory responses.
Abstract
Respiratory syncytial virus (RSV) causes substantial respiratory disease, while treatment is limited by drug resistance. Molecular docking of a 3,880-compound natural-product library identifies punicalin (PUN) as a dual-target RSV entry inhibitor. PUN inhibits the evaluated RSV-A and RSV-B strains, including a clinical isolate, and retains activity against strains resistant to ziresovir, ribavirin, nirsevimab, and palivizumab. After 20 passages under PUN selection, the half-maximal inhibitory concentration (IC50) increases 3.88-fold, remaining below the predefined >10-fold resistance threshold. Mechanistic analyses suggest that PUN interacts with the G protein cystine-noose region involving N178, N179, and W183 to inhibit attachment and with an F protein region involving V243, T245, and P246 to stabilize prefusion F and inhibit membrane fusion. These regions do not overlap known resistance hotspots. In RSV-infected mice, nebulized PUN provides sustained respiratory exposure, reduces lung viral loads and pathology, and attenuates inflammatory responses.
