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

Paolo Vincetti, Fabiana Caporuscio, Suzanne Kaptein, Antimo Gioiello, Valentina Mancino, Youichi Suzuki, Naoki Yamamoto, Emmanuele Crespan, Andrea Lossani, Giovanni Maga, Giulio Rastelli, Daniele Castagnolo, Johan Neyts, Pieter Leyssen, Gabriele Costantino, Marco Radi

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)4964-4975
JournalJournal of Medicinal Chemistry
Volume58
Issue number12
DOIs
Publication statusPublished - 3 Jun 2015

Fingerprint Dive into the research topics of 'Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn Kinases'. Together they form a unique fingerprint.

Cite this