Antiviral effect of oligo(nucleoside methylphosphonates) complementary to the herpes simplex virus type 1 immediate early mRNAs 4 and 5

Michael Kulka, Matthew Wachsman, Shunsuke Miura, Rita Fishelevich, Paul S. Miller, Paul O P Ts'o, Laure Aurelian

Research output: Contribution to journalArticle

Abstract

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 μM 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 μM). 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(pTCCTCCTGCGG). Virus growth was not inhibited by d(GpGCCCACGACAT). The data suggest that oligo(nucleoside methylphosphonates) may be effective antiviral agents.

Original languageEnglish (US)
Pages (from-to)115-130
Number of pages16
JournalAntiviral Research
Volume20
Issue number2
DOIs
StatePublished - 1993

Fingerprint

Human Herpesvirus 1
Nucleosides
Antiviral Agents
Messenger RNA
Growth
RNA Precursors
Viruses
Ficusin
RNA Splice Sites
Human Herpesvirus 2
Inhibitory Concentration 50
methylphosphonic acid
Cell Culture Techniques

Keywords

  • Antisense
  • Antiviral
  • HSV-1
  • Oligo(nucleoside methylphosphonates)

ASJC Scopus subject areas

  • Virology
  • Pharmacology

Cite this

Antiviral effect of oligo(nucleoside methylphosphonates) complementary to the herpes simplex virus type 1 immediate early mRNAs 4 and 5. / Kulka, Michael; Wachsman, Matthew; Miura, Shunsuke; Fishelevich, Rita; Miller, Paul S.; Ts'o, Paul O P; Aurelian, Laure.

In: Antiviral Research, Vol. 20, No. 2, 1993, p. 115-130.

Research output: Contribution to journalArticle

Kulka, Michael ; Wachsman, Matthew ; Miura, Shunsuke ; Fishelevich, Rita ; Miller, Paul S. ; Ts'o, Paul O P ; Aurelian, Laure. / Antiviral effect of oligo(nucleoside methylphosphonates) complementary to the herpes simplex virus type 1 immediate early mRNAs 4 and 5. In: Antiviral Research. 1993 ; Vol. 20, No. 2. pp. 115-130.
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T1 - Antiviral effect of oligo(nucleoside methylphosphonates) complementary to the herpes simplex virus type 1 immediate early mRNAs 4 and 5

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AU - Fishelevich, Rita

AU - Miller, Paul S.

AU - Ts'o, Paul O P

AU - Aurelian, Laure

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AB - 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 μM 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 μM). 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(pTCCTCCTGCGG). Virus growth was not inhibited by d(GpGCCCACGACAT). The data suggest that oligo(nucleoside methylphosphonates) may be effective antiviral agents.

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