Modelling the impact of JNJ-1802, a first-in-class dengue inhibitor blocking the NS3-NS4B interaction, on in-vitro DENV-2 dynamics

by Clare P. McCormack, Olivia Goethals, Nele Goeyvaerts, Xavier D. Woot de Trixhe, Peggy Geluykens, Doortje Borrenberghs, Neil M. Ferguson, Oliver Ackaert, Ilaria Dorigatti Dengue virus (DENV) is a public health challenge across the tropics and subtropics. Currently, there is no licensed prophylactic or antiviral treatment for dengue. The novel DENV inhibitor JNJ-1802 can significantly reduce viral load in mice and non-human primates. Here, using a mechanistic viral kinetic model calibrated against viral RNA data from experimentalin-vitro infection studies, we assess thein-vitro inhibitory effect of JNJ-1802 by characterising infection dynamics of two DENV-2 strains in the absence and presence of different JNJ-1802 concentrations. Viral RNA suppression to below the limit of detection was achieved at concentrations of>1.6 nM, with a median concentration exhibiting 50% of maximal inhibitory effect (IC50) of 1.23x10-02 nM and 1.28x10-02 nM for the DENV-2/RL and DENV-2/16681 strains, respectively. This work provides important insight into thein-vitro inhibitory effect of JNJ-1802 and presents a first step towards a modelling framework to support characterization of viral kinetics and drug effect across different host systems.
Source: PLoS Computational Biology - Category: Biology Authors: Source Type: research