P. F. Torrence*, W. Xiao, G. Li and S. Khamnei Pages 176 - 191 ( 16 )
The unique 2',5'-phosphodie.ster bond-linked oligonucleo tide known as 2-5A (Pn5'A2'(p5'A2')mp5'A) plays a key role in mediation of the anti-encephalomyocarditis virus action of interferon. 2-5A acts as a potent inhibitor of translation through the activation of a constituent latent endonuclease, the 2-5A-dependent ribonuclease (RNase) , which degrades RNAs. This 2-5A system, as part of a natural defense mechanism against virus infection, provides a paradigm for a new approach to the regulation of gene expression. Realization of this poten tial requires an understanding of the 2-5A oligoribonucleotide-associated structural parameters which govern its lifetime in biological systems and its interaction with the 2-5A-dependent ribonuclease responsible for RNA destruction. In this review, we describe the partial realization of such an understanding and the resulting development of a new approach to the specific and targeted cleavage of RNA by directing 2-5A-dependent RNase action to a precise target with an antisense DNA. The synthesis and mechanism of action of these novel composite nucleic acids permits exploration of the potent RNA destruction ability of the 2-5A-dependent RNase coupled with the specificity of antisense oligonucleotides as potential therapeutic agents for a variety of diseases.