Inhibition of Herpes Simplex Vims Replication by Antisense Oligo-2'-O-methylribonucleoside Methylphosphonates

Joanne M. Kean, Sarah A. Kipp, Paul S. Miller, Michael Kulka, Laure Aurelian

Research output: Contribution to journalArticle

Abstract

Antisense oligonucleoside methylphosphonates complementary to the 12 nucleotides found at the intron/exon junction of the splice acceptor site of herpes simplex virus type 1 (HSV-1) immediate early mRNAs 4 and 5 were synthesized. The methylphosphonate oligomers contained either 2'-deoxyribose nucleosides, d-OMPs, or 2'-O-methylribose nucleosides, mr-OMPs. At 37 °C, the affinity of the mr-OMP for a complementary 12-mer RNA target was approximately four times higher than that of the corresponding d-OMP as measured by a constant activity gel electrophoresis mobility shift assay. An mr-OMP whose sequence contained two mismatched bases did not bind to the RNA target under these conditions. The mr-OMP also showed improved ability to inhibit HSV-1 replication in HSV-1 infected Vero cells in culture. Thus the IC50 of the mr-OMP was five times less than that of the d-OMP. No inhibition was observed by the mismatched mr-OMP, and no inhibition of herpes simplex virus type 2 (HSV-2) replication was observed with any of the oligomers. These results demonstrate a direct correlation between oligomer binding affinity and antisense activity in cell culture and suggest that oligo-2'-O-methylribonucleoside methylphosphonates are promising candidates for development of effective antisense reagents.

Original languageEnglish (US)
Pages (from-to)14617-14620
Number of pages4
JournalBiochemistry
Volume34
Issue number45
DOIs
StatePublished - Nov 1995

ASJC Scopus subject areas

  • Biochemistry

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