Development of Peptide-Conjugated Morpholino Oligomers as Pan-Arenavirus Inhibitors

• Published in: Antimicrobial Agents and Chemotherapy Vol. 55; no. 10; pp. 4631 - 4638
• Main Authors: Neuman, Benjamin W, Bederka, Lydia H, Stein, David A, Ting, Joey P. C, Moulton, Hong M, Buchmeier, Michael J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01-10-2011
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral Agents; Antiviral Agents - pharmacology; antiviral properties; Arenaviridae; Arenaviridae Infections - drug therapy; Arenaviridae Infections - virology; Arenavirus; Arenavirus - drug effects; Arenavirus - genetics; Arenavirus - growth & development; Arenaviruses, New World - drug effects; Biological and medical sciences; Cell culture; Cell Line; Cercopithecus aethiops; fever; gene targeting; genome; Genome, Viral; Genomes; genomics; Hemorrhagic fever; in vivo studies; Junin virus; Junin virus - drug effects; Liver; Lymphocytic choriomeningitis virus; Lymphocytic choriomeningitis virus - drug effects; Medical sciences; Meningitis; Mice; Microbial Sensitivity Tests; Morpholinos; Morpholinos - pharmacology; Peptides; Peptides - pharmacology; Pharmacology. Drug treatments; Pichinde virus; Pichinde virus - drug effects; Protein Biosynthesis - drug effects; Public health; Replication; RNA; RNA, Viral - genetics; Tacaribe virus; Transcription; Translation; translation (genetics); Vero Cells; virus replication; Virus Replication - drug effects; viruses; Virus; Peptides; Development; Inhibitor; Morpholine derivatives; Oligomer; Arenaviridae; Arenavirus
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00650-11

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.