title: Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn Kinases.
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.
authors.affiliation: †P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vincetti
authors.affiliation: ‡Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Caporuscio
authors.affiliation: ∇Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kaptein
authors.affiliation: §Laboratory of Medicinal and Advanced Synthetic Chemistry (Lab MASC), Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo 1, I-06123 Perugia, Italy.
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.affiliation: §Laboratory of Medicinal and Advanced Synthetic Chemistry (Lab MASC), Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo 1, I-06123 Perugia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Mancino
authors.affiliation: ∥Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, 15-02, Level 15, Singapore 117599, Singapore.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: ∥Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, 15-02, Level 15, Singapore 117599, Singapore.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: ⊥Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.affiliation: ⊥Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lossani
authors.affiliation: ⊥Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.affiliation: ‡Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Rastelli
authors.affiliation: #Department of Applied Sciences, Northumbria University Newcastle, Ellison Place, NE1 8ST Newcastle upon Tyne, United Kingdom.
authors.forename: Daniele
authors.initials: D
authors.lastname: Castagnolo
authors.affiliation: ∇Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: ∇Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: †P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.affiliation: †P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D009033:Culicidae; D003715:Dengue / Q000188:drug therapy* / Q000378:metabolism; D003716:Dengue Virus / Q000187:drug effects* / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D060066:Protein Interaction Maps / Q000187:drug effects; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D020365:RNA Helicases / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D000081247:CSK Tyrosine-Protein Kinase; D051076:Proto-Oncogene Proteins c-fyn; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; D019061:src-Family Kinases; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C582223:NS5 protein, dengue virus; C000631346:CSK protein, human