title: A novel ribozyme-based prophylaxis inhibits influenza A virus replication and protects from severe disease.
abstract: Influenza A virus seasonal outbreaks and occasional pandemics represent a global health threat. The high genetic instability of this virus permits rapid escape from the host immune system and emergence of resistance to antivirals. There is thus an urgent need to develop novel approaches for efficient treatment of newly emerging strains. Based on a sequence alignment of representatives from every subtype known to infect humans, we identified nucleic acid regions that are conserved amongst these influenza A populations. We then engineered SOFA-HDV-Ribozymes as therapeutic tools recognizing these conserved regions to catalytically cleave the corresponding viral mRNA targets. The most promising ribozymes were chosen based on an initial in silico screening, and their efficacy was assessed using in vitro cleavage assays. Further characterization of their antiviral effect in cell culture and in mice led to the gradual identification of prophylactic SOFA-HDV-Ribozyme combinations, providing proof-of-principle for the potential of this novel strategy to develop antivirals against genetically highly variable viruses.
authors: Département de biochimie, RNA group/Groupe ARN, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Canada.
authors: Julie
authors: J
authors: Motard
authors: Ronan
authors: R
authors: Rouxel
authors: Alexandra
authors: A
authors: Paun
authors: Veronika
authors: V
authors: von Messling
authors: Martin
authors: M
authors: Bisaillon
authors: Jean-Pierre
authors: JP
authors: Perreault
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D055162:Biocatalysis; D005260:Female; D057809:HEK293 Cells; D003698:Hepatitis Delta Virus / Q000201:enzymology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D007251:Influenza, Human / Q000517:prevention & control* / Q000821:virology; D051379:Mice; D009698:Nucleoproteins / Q000378:metabolism; D016337:RNA, Catalytic / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D009698:Nucleoproteins; D016337:RNA, Catalytic; D012333:RNA, Messenger; D012367:RNA, Viral; D011994:Recombinant Proteins