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

PLoS Comput Biol. 2023 Dec 6;19(12):e1011662. doi: 10.1371/journal.pcbi.1011662. eCollection 2023 Dec.

Abstract

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 experimental in-vitro infection studies, we assess the in-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 the in-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.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Dengue Virus*
  • Dengue* / drug therapy
  • Mice
  • RNA, Viral / genetics
  • Virus Replication

Substances

  • JNJ-1802
  • RNA, Viral
  • Antiviral Agents