Targeted therapy of respiratory syncytial virus in African green monkeys by intranasally administered 2-5A antisense.
Respiratory syncytial virus (RSV) is a leading cause of respiratory disease in infants, young children, immunocompromised patients, and the institutionalized elderly. Previous work had shown that RNase L, an antiviral enzyme of the interferon system, could be recruited to cleave RSV genomic RNA by attaching tetrameric 2prime prime or minute-5prime prime or minute-linked oligoadenylates (2-5A) to an oligonucleotide complementary to repetitive gene-start sequences within the RSV genome (2-5A antisense). A 2prime prime or minute-O-methyl RNA-modified analog of the lead 2-5A anti-RSV chimera is shown here to have enhanced antiviral activity in cell culture studies while also cleaving RSV genomic RNA in an RNase L- and sequence-specific manner. When administered intranasally to RSV-infected African green monkeys, this chimera reduced nasal RSV replication by up to four log(10) units in a dose- and time-dependent manner.
Leaman
Douglas W
DW
Ridgeway Biosystems Inc., 9500 Euclid Avenue, NE50, Cleveland, Ohio 44195, USA. dleaman@utnet.utoledo.edu
Longano
Frank J
FJ
Okicki
James R
JR
Soike
Kenneth F
KF
Torrence
Paul F
PF
Silverman
Robert H
RH
Cramer
Hagen
H
D000227:Adenine Nucleotides; D000281:Administration, Intranasal; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004722:Endoribonucleases / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009843:Oligoribonucleotides; D012367:RNA, Viral / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
D000227:Adenine Nucleotides; D000998:Antiviral Agents; D016376:Oligonucleotides, Antisense; D009843:Oligoribonucleotides; D012367:RNA, Viral; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease