Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 12, Pages 4964-4975Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00108
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Funding
- University of Parma
- University of Perugia
- Research Project of National Interest Grant [PRIN2010W2KM5L_007]
- NUS SoM Start-Up Grant [R-182-000-160-733, R-182-000-160-133]
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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.
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