Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn Kinases

This
study describes the discovery of novel dengue virus inhibitors
targeting both a crucial viral protein–protein interaction
and an essential host cell factor as a strategy to reduce the emergence
of drug resistance. Starting from known c-Src inhibitors, a virtual
screening was performed to identify molecules able to interact with
a recently discovered allosteric pocket on the dengue virus NS5 polymerase.
The selection of cheap-to-produce scaffolds and the exploration of
the biologically relevant chemical space around them suggested promising
candidates for chemical synthesis. A series of purines emerged as
the most interesting candidates able to inhibit virus replication
at low micromolar concentrations with no significant toxicity to the
host cell. Among the identified antivirals, compound 16i proved to be 10 times more potent than ribavirin, showed a better
selectivity index and represents the first-in-class DENV-NS5 allosteric
inhibitor able to target both the virus NS5–NS3 interaction
and the host kinases c-Src/Fyn.