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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 25, 2015
• 年：2015
• 卷：58
• 期：12
• 页码：4964-4975
• 全文大小：464K
• ISSN：1520-4804

文摘

This study describes the discovery of novel dengue virus inhibitors targeting both a crucial viral protein鈥損rotein 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鈥揘S3 interaction and the host kinases c-Src/Fyn.