1. Broad spectrum compounds targeting early stages of rabies virus (RABV) infection
- Author
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Sabrina Kali, Saliha Azebi, Corinne Jallet, Juliana Pipoli Da Fonseca, Daniel Gillet, Jean-Christophe Cintrat, Noël Tordo, Thomas Cokelaer, Yu Wu, Julien Barbier, Stratégies antivirales, Institut Pasteur [Paris], Institut Pasteur d'Algérie, Réseau International des Instituts Pasteur (RIIP), Biomics (plateforme technologique), Neuro-Immunologie Virale - Viral Neuro-immunology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Chimie Bio-Organique et de Marquage (SCBM), Institut Pasteur de Guinée, The following programs contributed to fund the current research, both for material and fellowships: the joint ministerial program of R&D against CBRNE risks and Centre d’Energie Atomique (CEA - P/NRBC n°I1.1.8 'Large Spectrum Antivirals'), the European program ASKLEPIOS « Advanced Studies towards Knowledge on Lyssavirus Encephalitis Pathogenesis Improving Options for Survival » (FP7 - 602825 - Neglected infectious diseases of Central and Eastern Europe). In addition, the project benefited from the core facilities of the « Centre de Ressources et Recherches Technologiques » at the Institut Pasteur for imaging and bioinformatics., European Project: 602825,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,ASKLEPIOS(2013), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Benzylamines ,Indoles ,Endosome ,G protein ,[SDV]Life Sciences [q-bio] ,030106 microbiology ,Adamantane ,Endosomes ,Biology ,medicine.disease_cause ,Antiviral Agents ,Late endosome ,Cell Line ,Viral Proteins ,03 medical and health sciences ,Virology ,Drug Resistance, Viral ,Ribavirin ,Rabies glycoprotein ,medicine ,Animals ,Endosomal pathway inhibitors ,Pharmacology ,Rabies virus ,RNA ,Drug Synergism ,Virus Internalization ,Umifenovir ,medicine.disease ,Drug synergy ,3. Good health ,030104 developmental biology ,RAB7A ,Mutation ,Rabies ,medicine.drug - Abstract
International audience; ABMA and its analogue DABMA are two molecules of the adamantane family known to perturbate the endosomal pathway and to inhibit cell infection of several RNA and DNA viruses. Their activity against Rabies Virus (RABV) infection has already been demonstrated in vitro. (Wu et al., 2017, 2019). Here, we describe in more details their mechanism of action by comparison to Arbidol (umifenovir) and Ribavirin, two broad spectrum antivirals against emerging viruses such as Lassa, Ebola, influenza and Hantaan viruses. ABMA and DABMA, delivered 2 h pre-infection, inhibit RABV infection in vitro with an EC50 of 7.8 μM and 14 μM, respectively. They act at post-entry, by causing RABV accumulation within the endosomal compartment and DABMA specifically diminishes the expression of the GTPase Rab7a controlling the fusion of early endosomes to late endosomes or lysosomes. This may suggest that ABMA and DABMA act at different stages of the late endosomal pathway as supported by their different profile of synergy/antagonism with the fusion inhibitor Arbidol. This difference is further confirmed by the RABV mutants induced by successive passages under increasing selective pressure showing a particular involvement of the viral G protein in the DABMA inhibition while ABMA inhibition induces less mutations dispersed in the M, G and L viral proteins. These results suggest new therapeutic perspectives against rabies.
- Published
- 2021