Antiviral activity of a phosphorothioate oligonucleotide complementary to human cytomegalovirus RNA when used in combination with antiviral nucleoside analogs.
ISIS 2922 is a phosphorothioate oligonucleotide with potent antiviral activity against human cytomegalovirus (HCMV) in cell culture assays. The ability of ISIS 2922 to inhibit replication of HCMV when used in combination with other antiviral agents approved for treatment of HCMV disease was investigated using a 96-well immunoassay. The antiviral activity of ISIS 2922 against HCMV was additive with that of ganciclovir (9-(1,3-dihydroxy-2-propoxymethylguanine); DHPG) or foscarnet (phosphonoformate). Compounds used clinically for the treatment of human immunodeficiency virus infection and likely to be co-administered with ISIS 2922 in the clinic were also evaluated for their ability to modulate the antiviral activity of ISIS 2922. 3'-Azido-3'-deoxythymidine (AZT) exhibited no antiviral activity against HCMV in the 96-well immunoassay, and did not significantly alter the antiviral activity of ISIS 2922. 2'-3'-Dideoxycytidine (ddC) was able to inhibit replication of HCMV at high doses, and this activity was additive with that of ISIS 2922. ISIS 2922 inhibited HIV replication in acute infection assays at relatively high concentrations as previously reported for non-complementary phosphorothioate oligonucleotides. When ISIS 2922 was used in combination with AZT in this assay, interactions were additive at most concentrations, although significant and reproducible synergy was observed at some concentration combinations.
Azad
R F
RF
Department of Infectious Diseases, Isis Pharmaceuticals, Carlsbad, CA 92008, USA.
Brown-Driver
V
V
Buckheit
R W
RW
Anderson
K P
KP
D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics; D004347:Drug Interactions; D017245:Foscarnet / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D019384:Nucleic Acid Synthesis Inhibitors; D012367:RNA, Viral; D013873:Thionucleotides; D014779:Virus Replication / Q000187:drug effects; D016047:Zalcitabine / Q000031:analogs & derivatives / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D012367:RNA, Viral; D013873:Thionucleotides; D017245:Foscarnet; D015215:Zidovudine; D016047:Zalcitabine; C050624:2',3'-dideoxycytidinene; D015774:Ganciclovir; C091346:fomivirsen