Identification of potent inhibitors of arenavirus and SARS-CoV-2 exoribonucleases by fluorescence polarization assay
2022
Hernández, Sergio | Feracci, Mikael | de Jesus, Carolina Trajano | El Kazzi, Priscila | Kaci, Rafik | Garlatti, Laura | Mondielli, Clemence | Bailly, Fabrice | Cotelle, Philippe | Touret, Franck | de Lamballerie, Xavier | Coutard, Bruno | Decroly, Etienne | Canard, Bruno | Ferron, François | Alvarez, Karine | 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) | Evotec [Toulouse] | Lille Neurosciences & Cognition - U 1172 (LilNCog) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille) | Centrale Lille | Unité des Virus Emergents (UVE) ; Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM) | Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille) | ANR-18-ASTR-0010,PaNuVi,Les nucléases virales comme cibles thérapeutiques(2018)
International audience
Mostrar más [+] Menos [-]Inglés. Viral exoribonucleases are uncommon in the world of RNA viruses. To date, they have only been identified in the Arenaviridae and the Coronaviridae families. The exoribonucleases of these viruses play a crucial role in the pathogenicity and interplay with host innate immune response. Moreover, coronaviruses exoribonuclease is also involved in a proofreading mechanism ensuring the genetic stability of the viral genome. Because of their key roles in virus life cycle, they constitute attractive target for drug design.Here we developed a sensitive, robust and reliable fluorescence polarization assay to measure the exoribonuclease activity and its inhibition in vitro. The effectiveness of the method was validated on three different viral exoribonucleases, including SARS-CoV-2, Lymphocytic Choriomeningitis and Machupo viruses. We performed a screening of a focused library consisting of 113 metal chelators. Hit compounds were recovered with an IC50 at micromolar level. We confirmed 3 hits in SARS-CoV-2 infected Vero-E6 cells.
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