Site specificity of the inhibitory effects of oligo(nucleoside methylphosphonate)s complementary to the acceptor splice junction of herpes simplex virus type 1 immediate early mRNA 4.
Oligo(nucleoside methylphosphonate)s complementary to the splice junction of herpes simplex virus type 1 immediate early pre-mRNAs 4 and 5 caused specific inhibition of herpes simplex virus type 1 growth. The dodecamer d(TpTCCTCCTGCGG) (deoxynucleoside methylphosphonate residues in italic) caused 50% and 98% decreases in herpes simplex virus type 1 titers at concentrations of 15 microM and 100 microM, respectively. d(TpTCCTCCTGCGG) inhibited viral but not cellular protein synthesis and decreased splicing of immediate early pre-mRNAs 4 and 5. Inhibition was highly sequence specific. A psoralen derivative of d(TpTCCTCCTGCGG) that can covalently bind to complementary sequences after exposure to 365-nm irradiation caused 90-98% inhibition of virus growth in cells treated with oligomer (5 microM) and irradiated at 1-3 hr postinfection. The data suggest that oligo(nucleoside methylphosphonate)s of appropriate sequence and derivatization may be effective as antiviral agents.
Kulka
M
M
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
Smith
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Aurelian
L
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Fishelevich
R
R
Meade
K
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Miller
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Ts'o
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D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D005091:Exons; D005814:Genes, Viral; D007438:Introns; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000494:pharmacology*; D063065:Organophosphonates / Q000494:pharmacology; D014176:Protein Biosynthesis; D012326:RNA Splicing / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D012367:RNA, Viral / Q000187:drug effects / Q000235:genetics*; D018139:Simplexvirus / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development; D014466:Ultraviolet Rays; D014709:Vero Cells
D009841:Oligonucleotides; D063065:Organophosphonates; D012333:RNA, Messenger; D012367:RNA, Viral