Antiviral effect of oligo(nucleoside methylphosphonates) complementary to the herpes simplex virus type 1 immediate early mRNAs 4 and 5.
We have previously shown that an oligo(nucleoside methylphosphonate) (deoxynucleoside methylphosphonate residues in italics) complementary to the acceptor splice junction of herpes simplex virus type 1 (HSV-1) immediate-early (IE) pre-mRNAs 4,5 [d(TpTCCTCCTGCGG)], causes sequence-specific inhibition of virus growth in infected cell cultures (Smith et al., 1986; Kulka et al., 1989). Here we report a similar inhibition of HSV-1 growth by oligo(nucleoside methylphosphonates) complementary to the splice donor site of HSV-1 IE pre-mRNAs 4,5 [d(GpCTTACCCGTGC)] and to the translation initiation site of IE4 mRNA [d(ApATGTCGGCCAT)]. An oligomer complementary to the translation initiation site of IE5 mRNA [d(GpGCCCACGACAT)] or an unrelated oligomer [d(GpCGGGAAGGCAC)] did not inhibit virus growth. IC50 values were 20, 25 and 20 microM for d(TpTCCTCCTGCGG), d(GpCTTACCCGTGC) and d(ApATGTCGGCCAT) respectively. In infected BALB/c mice d(TpTCCTCCTGCGG) caused a significant decrease in HSV-1 growth (82% inhibition at 500 microM). A psoralen-derivative of d(TpTCCTCCTGCGG) that binds covalently to complementary sequences after exposure to 365 nm irradiation, inhibited HSV-1 growth (86-91%) at a 10-fold lower concentration than the non-derivatized oligomer. The inhibition was sequence-specific and significantly lower (27%) for HSV-2 that differs from HSV-1 in 7 of the 12 bases targeted by d(TpTCCTCCTGCGG). Virus growth was not inhibited by d(GpGCCCACGACAT). The data suggest that oligo(nucleoside methylphosphonates) may be effective antiviral agents.
Kulka
M
M
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
Wachsman
M
M
Miura
S
S
Fishelevich
R
R
Miller
P S
PS
Ts'o
P O
PO
Aurelian
L
L
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D005814:Genes, Viral / Q000187:drug effects*; D006561:Herpes Simplex / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects*; D012367:RNA, Viral / Q000187:drug effects*; D018139:Simplexvirus / Q000187:drug effects*; D014709:Vero Cells
D000998:Antiviral Agents; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D012367:RNA, Viral