title: Development of peptide-conjugated morpholino oligomers as pan-arenavirus inhibitors.
abstract: Members of the Arenaviridae family are a threat to public health and can cause meningitis and hemorrhagic fever, and yet treatment options remain limited by a lack of effective antivirals. In this study, we found that peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) complementary to viral genomic RNA were effective in reducing arenavirus replication in cell cultures and in vivo. PPMO complementary to the Junín virus genome were designed to interfere with viral RNA synthesis or translation or both. However, only PPMO designed to potentially interfere with translation were effective in reducing virus replication. PPMO complementary to sequences that are highly conserved across the arenaviruses and located at the 5' termini of both genomic segments were effective against Junín virus, Tacaribe virus, Pichinde virus, and lymphocytic choriomeningitis virus (LCMV)-infected cell cultures and suppressed viral titers in the livers of LCMV-infected mice. These results suggest that arenavirus 5' genomic termini represent promising targets for pan-arenavirus antiviral therapeutic development.
authors.affiliation: University of Reading, Reading RG6 6AJ, United Kingdom.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Neuman
authors.forename: Lydia H
authors.initials: LH
authors.lastname: Bederka
authors.forename: David A
authors.initials: DA
authors.lastname: Stein
authors.forename: Joey P C
authors.initials: JP
authors.lastname: Ting
authors.forename: Hong M
authors.initials: HM
authors.lastname: Moulton
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Buchmeier
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001117:Arenaviridae Infections / Q000188:drug therapy / Q000821:virology; D018050:Arenavirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006477:Arenaviruses, New World / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D016679:Genome, Viral; D018051:Junin virus / Q000187:drug effects; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D060172:Morpholinos / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D018052:Pichinde virus / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D012367:RNA, Viral / Q000235:genetics; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D060172:Morpholinos; D010455:Peptides; D012367:RNA, Viral