title: Natural compounds isolated from Brazilian plants are potent inhibitors of hepatitis C virus replication in vitro.
abstract: Compounds extracted from plants can provide an alternative approach to new therapies. They present characteristics such as high chemical diversity, lower cost of production and milder or inexistent side effects compared with conventional treatment. The Brazilian flora represents a vast, largely untapped, resource of potential antiviral compounds. In this study, we investigate the antiviral effects of a panel of natural compounds isolated from Brazilian plants species on hepatitis C virus (HCV) genome replication. To do this we used firefly luciferase-based HCV sub-genomic replicons of genotypes 2a (JFH-1), 1b and 3a and the compounds were assessed for their effects on both HCV replication and cellular toxicity. Initial screening of compounds was performed using the maximum non-toxic concentration and 4 compounds that exhibited a useful therapeutic index (favourable ratio of cytotoxicity to antiviral potency) were selected for extra analysis. The compounds APS (EC50=2.3μM), a natural alkaloid isolated from Maytrenus ilicifolia, and the lignans 3(∗)43 (EC50=4.0μM), 3(∗)20 (EC50=8.2μM) and 5(∗)362 (EC50=38.9μM) from Peperomia blanda dramatically inhibited HCV replication as judged by reductions in luciferase activity and HCV protein expression in both the subgenomic and infectious systems. We further show that these compounds are active against a daclatasvir resistance mutant subgenomic replicon. Consistent with inhibition of genome replication, production of infectious JFH-1 virus was significantly reduced by all 4 compounds. These data are the first description of Brazilian natural compounds possessing anti-HCV activity and further analyses are being performed in order to investigate the mode of action of those compounds.
authors.affiliation: UFU - Federal University of Uberlândia, Institute of Biomedical Science - ICBIM, Uberlândia, MG, Brazil; UNESP - São Paulo State University, Institute of Bioscience, Language and Exact Science - IBILCE, Department of Biology, São José do Rio Preto, SP, Brazil. Electronic address: caroljardim@gmail.com.
authors.forename: A C G
authors.initials: AC
authors.lastname: Jardim
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom. Electronic address: z.Igloi@leeds.ac.uk.
authors.forename: Z
authors.initials: Z
authors.lastname: Igloi
authors.affiliation: UNESP - São Paulo State University, Institute of Bioscience, Language and Exact Science - IBILCE, Department of Biology, São José do Rio Preto, SP, Brazil. Electronic address: jacquelineshimizu@gmail.com.
authors.forename: J F
authors.initials: JF
authors.lastname: Shimizu
authors.affiliation: UNESP - São Paulo State University, Institute of Chemistry, Department of Organic Chemistry, Araraquara, SP, Brazil. Electronic address: vaniaapf@gmail.com.
authors.forename: V A F F M
authors.initials: VA
authors.lastname: Santos
authors.affiliation: UNESP - São Paulo State University, Institute of Chemistry, Department of Organic Chemistry, Araraquara, SP, Brazil. Electronic address: lidiane_iq@yahoo.com.br.
authors.forename: L G
authors.initials: LG
authors.lastname: Felippe
authors.affiliation: UNESP - São Paulo State University, Institute of Bioscience, Language and Exact Science - IBILCE, Department of Biology, São José do Rio Preto, SP, Brazil. Electronic address: bruna.mazzeu@gmail.com.
authors.forename: B F
authors.initials: BF
authors.lastname: Mazzeu
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Electronic address: amako-yt@igakuken.or.jp.
authors.forename: Y
authors.initials: Y
authors.lastname: Amako
authors.affiliation: UNESP - São Paulo State University, Institute of Chemistry, Department of Organic Chemistry, Araraquara, SP, Brazil. Electronic address: mayfurlan@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Furlan
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom. Electronic address: m.harris@leeds.ac.uk.
authors.forename: M
authors.initials: M
authors.lastname: Harris
authors.affiliation: UNESP - São Paulo State University, Institute of Bioscience, Language and Exact Science - IBILCE, Department of Biology, São José do Rio Preto, SP, Brazil. Electronic address: prahal@ibilce.unesp.br.
authors.forename: P
authors.initials: P
authors.lastname: Rahal
mesh_terms: D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000998:Antiviral Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001938:Brazil; D045744:Cell Line, Tumor; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D017705:Lignans / Q000302:isolation & purification / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D036941:Peperomia / Q000737:chemistry; D031701:Piper / Q000737:chemistry; D010944:Plants / Q000737:chemistry*; D012093:Replicon / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000470:Alkaloids; D000998:Antiviral Agents; D017705:Lignans
keywords: Antiviral; Brazilian plants; Hepatitis C virus; Natural compounds; Replication