title: Evaluation of Crimean-Congo hemorrhagic fever virus in vitro inhibition by chloroquine and chlorpromazine, two FDA approved molecules.
abstract: Crimean-Congo hemorrhagic virus (CCHFV) causes hemorrhagic fever with high case mortality rates and is endemic in south-eastern Europe, Africa, and Asia. The limited catalog of specific treatment, highlight the necessity to look for additional therapeutic solutions. Previous experiments suggested that CCHFV enters the cells via a clathrin dependent pathway. Therefore, we have evaluated the potential anti-CCHFV activity of several molecules targeting this entry possibility. We identified two molecules chloroquine and chlorpromazine. Neutralization and virus yield reduction assays were tested in Vero E6 and Huh7 cells on two different CCHFV strains. Several combinations, including ribavirin, were assayed to test a potential synergistic effect. The two molecules inhibited CCHFV, and depending on the virus and the cell lines, the 50% inhibitory concentration (IC50) values for chloroquine and chlorpromazine ranged from 28 to 43 and 10.8-15.7 μM, respectively. Time-of-addition studies demonstrated that these molecules had a direct effect on CCHFV infectivity and spread. The antiviral activity of the two molecules was still effective even when added up to 6h post-infection and up to 24h. The selectivity index ranging from 3 to 35 lead us to evaluate combinations with ribavirin. Combinations of ribavirin and chloroquine or chlorpromazine were synergistic against CCHFV. Though the low chlorpromazine selectivity index suggests the need for a chemical improvement, our present study highlights chloroquine as the main drug having the potential for drug repurposing.
authors: Institut de Recherche Biomédicale des Armées, Unité de Virologie, Lyon, France.
authors: O
authors: O
authors: Ferraris
authors: Fondation Mérieux, Laboratoire des Pathogènes Émergents, Lyon, France.
authors: M
authors: M
authors: Moroso
authors: Unité de Virologie Humaine - INSERM U758, Lyon, France.
authors: O
authors: O
authors: Pernet
authors: Institut de Recherche Biomédicale des Armées, Unité de Virologie, Lyon, France.
authors: S
authors: S
authors: Emonet
authors: Institut de Recherche Biomédicale des Armées, Unité de Virologie, Lyon, France.
authors: A
authors: A
authors: Ferrier Rembert
authors: Fondation Mérieux, Laboratoire des Pathogènes Émergents, Lyon, France.
authors: G
authors: G
authors: Paranhos-Baccalà
authors: Institut de Recherche Biomédicale des Armées, Unité de Virologie, Lyon, France; Fondation Mérieux, Laboratoire des Pathogènes Émergents, Lyon, France.
authors: C N
authors: CN
authors: Peyrefitte
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology*; D002746:Chlorpromazine / Q000494:pharmacology*; D058492:Drug Repositioning; D004357:Drug Synergism; D003225:Hemorrhagic Fever Virus, Crimean-Congo / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D012254:Ribavirin / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin; D002738:Chloroquine; D002746:Chlorpromazine
keywords: Antiviral; Chloroquine; Chlorpromazine; Crimean-Congo hemorrhagic fever virus; Ribavirin