Metal chelators for the inhibition of the lymphocytic choriomeningitis virus endonuclease domain

Autor: Magali Saez-Ayala, François Ferron, Dominga Rogolino, Elsie Laban Yekwa, Loic Roux, Clémence Mondielli, Sergio Hernández, Karine Alvarez, Bruno Canard, Fabrice Bailly, Philippe Cotelle
Přispěvatelé: 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), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, University of Parma = Università degli studi di Parma [Parme, Italie], Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondation pour la Recherche Medicale SPF20130526788, ANR-11-BSV8-0019,ArenaBunya-L,Structures, mecanismes, et conception d'inhibiteurs des protéines L des Bunyavirus et Arenavirus(2011), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog), Università degli studi di Parma = University of Parma (UNIPR)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Arenaviridae
[SDV]Life Sciences [q-bio]
030106 microbiology
Diketo acids
Metal chelators
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
Virus Replication
Lymphocytic choriomeningitis
Virus
Small Molecule Libraries
3-diones
Viral Proteins
03 medical and health sciences
Endonuclease
Virology
medicine
Lymphocytic choriomeningitis virus
[CHIM]Chemical Sciences
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
LCMV
Chelating Agents
Pharmacology
Arenavirus
biology
Chemistry
Microscale thermophoresis
Drug discovery
[CHIM.ORGA]Chemical Sciences/Organic chemistry
Polyphenols
Endonucleases
medicine.disease
biology.organism_classification
High-Throughput Screening Assays
3. Good health
N-Hydroxyisoquinoline-1
030104 developmental biology
Biochemistry
[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology
biology.protein
Arenavirus Metal chelators LCMV Endonuclease domain Diketo acids Polyphenols N-Hydroxyisoquinoline-1
Pharmacophore
Endonuclease domain
Zdroj: Antiviral Research
Antiviral Research, Elsevier Masson, 2019, 162, pp.79-89. ⟨10.1016/j.antiviral.2018.12.008⟩
Antiviral Research, 2019, 162, pp.79-89. ⟨10.1016/j.antiviral.2018.12.008⟩
ISSN: 0166-3542
DOI: 10.1016/j.antiviral.2018.12.008⟩
Popis: International audience; Arenaviridae is a viral family whose members are associated with rodent-transmitted infections to humans responsible of severe diseases. The current lack of a vaccine and limited therapeutic options make the development of efficacious drugs of high priority. The cap-snatching mechanism of transcription of Arenavirus performed by the endonuclease domain of the L-protein is unique and essential, so we developed a drug design program targeting the endonuclease activity of the prototypic Lymphocytic ChorioMeningitis Virus. Since the endonuclease activity is metal ion dependent, we designed a library of compounds bearing chelating motifs (diketo acids, polyphenols, and N-hydroxyisoquinoline-1,3-diones) able to block the catalytic center through the chelation of the critical metal ions, resulting in a functional impairment. We pre-screened 59 compounds by Differential Scanning Fluorimetry. Then, we characterized the binding affinity by Microscale Thermophoresis and evaluated selected compounds in in vitro and in cellula assays. We found several potent binders and inhibitors of the endonuclease activity. This study validates the proof of concept that the endonuclease domain of Arenavirus can be used as a target for anti-arena-viral drug discovery and that both diketo acids and N-hydroxyisoquinoline-1,3-diones can be considered further as potential metal-chelating pharmacophores.
Databáze: OpenAIRE
Externí odkaz: