Antiviral effect of an oligo(nucleoside methylphosphonate) complementary to the splice junction of herpes simplex virus type 1 immediate early pre-mRNAs 4 and 5.
Selective inhibition of regulatory immediate early (IE) genes of herpes simplex virus type 1 (HSV-1) should inhibit virus growth. Treatment of HSV-1-infected cells with the oligo(nucleoside methylphosphonate) d(TpCCTCCTG) (deoxynucleoside methylphosphonate residues in italic), which is complementary to the acceptor splice junction of HSV-1 IE pre-mRNA 4 and 5, before (1-24 hr) or at the time of infection caused a dose-dependent inhibition in virus replication. Virus titers were decreased 50% and 90% in cells treated with 25 microM and 75 microM oligomer, respectively; at 300 microM, a 99% reduction in virus production was observed. Viral DNA synthesis was reduced 70-75% and there was a 90% reduction in synthesis of viral proteins, including other IE species and viral functional (130-kDa major DNA-binding) and structural (glycoprotein gB) proteins. In the same concentration range, d(TpCCTCCTG) caused a minimal reduction (0-30%) in protein synthesis and growth rates (less than 40%) of uninfected cells. The data suggest that oligo(nucleoside methylphosphonate)s may be effective in antiviral chemotherapy.
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D004279:DNA, Viral / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005816:Genetic Complementation Test; D006801:Humans; D009694:Nucleic Acid Precursors / Q000378:metabolism*; D009841:Oligonucleotides / Q000494:pharmacology*; D014176:Protein Biosynthesis; D012322:RNA Precursors; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*; D018139:Simplexvirus / Q000187:drug effects* / Q000235:genetics; D014764:Viral Proteins / Q000096:biosynthesis
D000998:Antiviral Agents; D004279:DNA, Viral; D009694:Nucleic Acid Precursors; D009841:Oligonucleotides; D012322:RNA Precursors; D012333:RNA, Messenger; D014764:Viral Proteins