title: Potent inhibition of respiratory syncytial virus by combination treatment with 2-5A antisense and ribavirin.
abstract: Respiratory syncytial virus (RSV) is a major cause of lower respiratory diseases in infants, young children, and the elderly. Ribavirin, the only currently approved drug for the treatment of RSV infections in the U.S., requires high doses to be effective. Therefore, it has only a limited clinical efficacy in the treatment of RSV infections. It has been shown that a cellular ribonuclease, RNase L, can be recruited by 2'-5' linked tetra-adenylates (2-5A) attached to an antisense sequence complementary to the RSV genome to specifically cleave RSV genomic RNA. Here we confirm the antiviral activity of the lead 2-5A antisense compound, RBI034, by using several different viral assays. We demonstrate that RBI034 is more efficient than antisense lacking 2-5A or small interfering dsRNA (siRNA) in inhibiting RSV replication. Although the best antiviral activity of RBI034 was observed with co-treatment of RSV infection, it remained effective even when administered 24 h after the initiation of infection. Interestingly, the activity of RBI034 can be further enhanced by a combination treatment with ribavirin. At suboptimal concentrations, neither ribavirin nor RBI034 was effective in suppressing RSV replication. However, a combination of these two drugs at the same suboptimal concentrations showed a potent inhibitory activity. The potent reduction of RSV replication by combination treatment was also confirmed in primary human airway epithelial cells. Therefore, a combination therapy of the 2-5A antisense compound RBI034 and ribavirin might be a more effective therapeutic approach for treating RSV infections than ribavirin alone.
authors.affiliation: Ridgeway Biosystems, Inc., 9500 Euclid Avenue, ND50, Cleveland, OH 44195, USA. xuz@ridgewaybio.com
authors.forename: Zan
authors.initials: Z
authors.lastname: Xu
authors.forename: Mei
authors.initials: M
authors.lastname: Kuang
authors.forename: James R
authors.initials: JR
authors.lastname: Okicki
authors.forename: Hagen
authors.initials: H
authors.lastname: Cramer
authors.forename: Nilabh
authors.initials: N
authors.lastname: Chaudhary
mesh_terms: D000227:Adenine Nucleotides / Q000737:chemistry*; D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004847:Epithelial Cells / Q000821:virology; D006801:Humans; D009843:Oligoribonucleotides / Q000737:chemistry*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D012367:RNA, Viral / Q000032:analysis; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000254:growth & development; D012254:Ribavirin / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000227:Adenine Nucleotides; D000998:Antiviral Agents; D009843:Oligoribonucleotides; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012367:RNA, Viral; D012254:Ribavirin; C023505:2',5'-oligoadenylate