Here using an active-site-directed aminopyrrolidineamide-based inhibitor of SKI-1/S1P, PF-429242 [25], we demonstrated that inhibition of host SKI-1/S1P enzymatic activity effectively blocks DENV (1–4) from establishing infection in human hepatoma Huh-7.5.1 cells. Here, MBTPS1 is linked to infection.