Inhibition of viral growth by an alpha-oligonucleotide directed to the splice junction of herpes simplex virus type-1 immediate-early pre-mRNA species 22 and 47.

Abstract

A 13-residue alpha-anomeric oligonucleotide [alpha-5'-d(GGGCGTCCTCCTT)3'], 5'-substituted with a psoralen derivative, Pso-alpha-13 psoralen linked to the 5' end of an alpha-anomeric n-residue oligonucleotide, was targeted to the acceptor splice junction of Herpes simplex virus type-1 immediate-early pre-mRNA species 22 and 47. Inhibition of viral growth was observed upon irradiation of Vero cells infected with Herpes simplex virus type-1 and treatment with Pso-alpha-13. The virus titer was decreased by 80% at an oligonucleotide concentration of 0.5 microM and at a multiplicity of infection of 0.1 plaque-forming units/cell. The 13-residue oligonucleotide did not induce any cytotoxic effect after irradiation and the inhibition of viral growth was clearly sequence specific. A non-specific 5' Pso-alpha-15 did not inhibit Herpes simplex virus type-1 growth. The 5' Pso-alpha-13 targeted to the acceptor splice junction of Herpes simplex virus type 1, contained five mismatches with respect to the corresponding sequence of Herpes simplex virus type 2, and did not exhibit any inhibitory effects on Herpes simplex virus type-2 growth. These results show that alpha-oligonucleotides can exhibit a sequence-specific antiviral effect and suggest that they may inhibit splicing reactions and be useful in targeting specific nucleic acid sequences within the cell nucleus.