Inhibition of herpes simplex virus type 2 growth by phosphorothioate oligodeoxynucleotides.
Phosphorothioate homo-oligodeoxynucleotides were found to be potent inhibitors of herpes simplex virus type 2 (HSV-2) but less potent for HSV-1 in cell culture studies. Oligomers with longer chain lengths were more active against HSV-2 than those with shorter ones. Of all the compounds examined, the 28-mer phosphorothioate homo-oligodeoxynucleotides were the strongest inhibitors of HSV-2. The degree of inhibition was related to the base moiety on the order of deoxycytidine = thymidine greater than deoxyadenosine. The inhibition of HSV-2 growth by S-dC28 was dose dependent with a 90% inhibitory dose of 1 microM. At 50 microM, S-dC28 inhibited HeLa S3 cell growth by less than 10%. The anti-HSV-2 activity was time and schedule dependent. The oligomer was most inhibitory to viral growth when present during the 1-h viral adsorption period, and this effect could be enhanced by continuous drug exposure after the adsorption period. S-dC28 was also an effective inhibitor of two HSV-2 drug-resistant mutants: a phosphonoformate-resistant mutant that induces an altered DNA polymerase and a 9-(1,3-dihydroxy-2-propoxymethyl)guanine-resistant mutant that does not induce the viral thymidine kinase. In drug combination studies, phosphonoformate was shown to potentiate the action of S-dC28 against HSV-2 growth. In conclusion, because of their potency and selectivity, phosphorothioate homo-oligodeoxynucleotides are a promising new class of anti-HSV agents.
Gao
W Y
WY
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
Hanes
R N
RN
Vazquez-Padua
M A
MA
Stein
C A
CA
Cohen
J S
JS
Cheng
Y C
YC
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D009841:Oligonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense; D018139:Simplexvirus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D013873:Thionucleotides / Q000494:pharmacology*; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides