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

Vincetti, Paolo, Caporuscio, Fabiana, Kaptein, Suzanne, Gioiello, Antimo, Mancino, Valentina, Suzuki, Youichi, Yamamoto, Naoki, Crespan, Emmanuele, Lossani, Andrea, Maga, Giovanni, Rastelli, Giulio, Castagnolo, Daniele, Neyts, Johan, Leyssen, Pieter, Costantino, Gabriele and Radi, Marco (2015) Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn Kinases. Journal of Medicinal Chemistry, 58 (12). pp. 4964-4975. ISSN 0022-2623

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Official URL: http://dx.doi.org/10.1021/acs.jmedchem.5b00108

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.

Item Type: Article
Subjects: A300 Clinical Medicine
C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > School of Life Sciences > Applied Sciences
Depositing User: Paul Burns
Date Deposited: 20 Jul 2015 14:58
Last Modified: 21 Jul 2016 08:32
URI: http://nrl.northumbria.ac.uk/id/eprint/23400

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