Arenaviridae NP-exonuclease inhibition by bisphosphonate
2022
Hong van Nguyen, Thi | Yekwa, Elsie | Selisko, Barbara | Canard, Bruno | Alvarez, Karine | Ferron, Francois | Architecture et fonction des macromolécules biologiques (AFMB) ; Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | Aix Marseille Université (AMU) | European Virus Bioinformatics Center [Jena] | ANR-11-BSV8-0019,ArenaBunya-L,Structures, mecanismes, et conception d'inhibiteurs des protéines L des Bunyavirus et Arenavirus(2011) | ANR-18-ASTR-0010,PaNuVi,Les nucléases virales comme cibles thérapeutiques(2018) | ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010) | European Project: 260644,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,SILVER(2010)
International audience
Show more [+] Less [-]English. Arenaviruses are emerging enveloped negative-sense RNA viruses which cause neurological and hemorrhagic diseases in humans. Currently there is no FDA approved vaccine or therapeutic agent except ribavirin which must be administered early during infection for optimum efficacy. A hallmark for arenavirus infection is a rapid and efficient immune-suppression mediated by the exonuclease domain encoded by the nucleoprotein. This exonuclease is therefore an attractive target for the design of novel antiviral drugs since exonuclease inhibitors might not only have a direct effect on the enzyme but could also boost viral clearance through stimulation of the innate immune system of the host cell. Here we have used an in silico screening and an enzymatic assay to identify a novel, specific but weak inhibitor of the arenavirus exonuclease with IC 50 values of 65.9 µM and 68.6 µM for Mopeia virus and Lymphocytic choriomeningitis virus, respectively. We further characterized this finding with crystallographic and docking approaches. This study serves as a proof of concept and may have assigned a new therapeutic purpose for the bisphosphonate family and therefore paves the way for the development of inhibitors against Arenaviridae.
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