Fig. 1: The molecular structure, in vitro pan-genotype and -serotype activity, and mechanism of action of JNJ-1802.
From: Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates
a, The molecular structure of JNJ-1802. b, In vitro antiviral activity in Vero E6 cells against a panel of clinical isolates23. Data are mean EC50 values. The asterisk and hash symbols indicate that the DENV strain carries a T108I (*) or T108A (#) mutation in NS4B. Where indicated by a triangle, the mean EC50 in Vero E6 cells was calculated by setting the values below the 0.04 nM threshold at 0.04 nM. A, American; AA, Asian American; AI, Asian I; AII, Asian II; C, cosmopolitan; S, sylvatic. c, Schematic of the DENV NS4B membrane topology50,51. JNJ-1802-selected resistance mutations in orange were present in at least 99% of the quasispecies at the end point (passage 42 (sample A); passage 50 (sample B)). Mutations in black were present in less than 50% of the quasispecies at the end point. Mutations in blue appeared transiently and had disappeared at the end of the experiment. The diagram was created in part using the Servier Medical Art library (https://smart.servier.com/). d, JNJ-1802 prevents DENV NS3–NS4B interaction. Three independent co-immunoprecipitation experiments were performed to establish the JNJ-1802 dose–response curve for the NS3–NS4B interaction. Representative western blots are shown in Extended Data Fig. 2a,b. Signal intensity ratios were determined as described in the Methods. Data are mean ± s.e.m. For the comparison of NS3:NS4B–HA ratios between JNJ-1802 treated samples and DMSO control, P values were calculated using repeated-measures one-way analysis of variance (ANOVA) with subsequent Dunnett’s multiple-comparisons test; NS, not significant. EC50, 50% effective concentration; DMSO, dimethyl sulfoxide; IP, immunoprecipitation; TM, transmembrane.
