Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design

The
discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA
polymerase (RdRp) inhibitors are described. An X-ray-based fragment
screen of Novartis’ fragment collection resulted in the identification
of a biphenyl acetic acid fragment 3, which bound in
the palm subdomain of RdRp. Subsequent optimization of the fragment
hit 3, relying on structure-based design, resulted in
a >1000-fold improvement in potency in vitro and acquired antidengue
activity against all four serotypes with low micromolar EC50 in cell-based assays. The lead candidate 27 interacts
with a novel binding pocket in the palm subdomain of the RdRp and
exerts a promising activity against all clinically relevant dengue
serotypes.