A trichlorobenzene-substituted azaaryl compound MTP0L145 blocks endosomal acidification to inhibit dengue virus infection

Abstract

Abstract Blocking endosomal acidification retards dengue virus (DENV) infection. A trichlorobenzene-substituted azaaryl compound MTP0L145, originally designed as a novel fibroblast growth factor receptor (FGFR) inhibitor, confers an unexpected inhibition on endosomal acidification. Here, we examined for the blockade of DENV infection by MTP0L145. As similar to Bafilomycin A1, treatment of FGFR inhibitors MTP0L145 and BGJ39 all cause a blocking effect on endosomal acidification in cells with DENV infection. Inhibiting FGFR significantly causes inhibition on DENV infection, including dsRNA replication, protein expression, and virus release, but not viral entry as well as translation directly. FGFR antagonist NSC12, a blocker of FGF and FGFR interaction, neither inhibits viral entry nor causes blocking effects on endosomal acidification and viral replication, indicating a ligand-independent involvement. MTP0L145 and BGJ-398 inhibit receptor tyrosine kinase activity in FGFRs following DENV infection. Activation of vacuolar-type H+-ATPase for endosomal activation requires FGFR-mediated PI3-kinase/Akt and MAPK activation. Inhibiting the FGFR signaling pathway effectively retards DENV infection and mortality. These results demonstrate that MTP0L145 treatment reduces DENV infection principally by retarding FGFR-regulated endosomal acidification. This study was supported by grants from the Ministry of Science and Technology (MOST108-2320-B-038-026), Taipei, Taiwan.