Inhibition of hepatitis C virus replication and internal ribosome entry site-dependent translation by an RNA molecule.
Hepatitis C virus (HCV) protein synthesis is mediated by a highly conserved internal ribosome entry site (IRES), mostly located at the 5' untranslatable region (UTR) of the viral genome. The translation mechanism is different from that used by cellular cap-mRNAs, making IRESs an attractive target site for new antiviral drugs. The present work characterizes a chimeric RNA molecule (HH363-50) composed of two inhibitors: a hammerhead ribozyme targeting position 363 of the HCV genome and an aptamer directed towards the essential stem-loop structure in domain IV of the IRES region (which contains the translation start codon). The inhibitor RNA interferes with the formation of a translationally active complex, stalling its progression at the level of 80S particle formation. This action is likely related to the effective and specific blocking of HCV IRES-dependent translation achieved in Huh-7 cells. The inhibitor HH363-50 also reduces HCV RNA levels in a subgenomic replicon system. The present findings suggest that HH363-50 could be an effective anti-HCV compound and highlight the possibilities of antiviral agents based on RNA molecules.
Romero-López
Cristina
C
Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, Parque Tecnológico de Ciencias de la Salud, Avda del Conocimiento s/n, Armilla, 18100 Granada, Spain.
Díaz-González
Raquel
R
Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, Parque Tecnológico de Ciencias de la Salud, Avda del Conocimiento s/n, Armilla, 18100 Granada, Spain.
Barroso-delJesus
Alicia
A
Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, Parque Tecnológico de Ciencias de la Salud, Avda del Conocimiento s/n, Armilla, 18100 Granada, Spain.
Berzal-Herranz
Alfredo
A
Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, Parque Tecnológico de Ciencias de la Salud, Avda del Conocimiento s/n, Armilla, 18100 Granada, Spain.
D000998:Antiviral Agents / Q000494:pharmacology*; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D014176:Protein Biosynthesis / Q000187:drug effects*; D012313:RNA / Q000494:pharmacology*; D016337:RNA, Catalytic / Q000494:pharmacology; D012367:RNA, Viral / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D052157:Aptamers, Nucleotide; D016337:RNA, Catalytic; D012367:RNA, Viral; C427204:hammerhead ribozyme; D012313:RNA