Chemistry and biochemistry of 2 ',5 '-oligoadenylate-based antisense strategy

This review describes the application of a natural defense mechanism to dev elop effective agents for the post-transcriptional control of gene expressi on. 2-5A is a unique 2 ' ,5 ' -phosphodiester bond linked oligoadenylate, ( pp)p5 ' A2 ' (p5 'A)(n) , that is elaborated in virus-infected interferon-t reated cells. The 2-5A system is an RNA degradation pathway that is an impo rtant mechanistic component of interferon's action against certain viruses. It may also play a role in the anticellular effects of interferon and in g eneral RNA decay. A major player in the 2-5A-system is the latent and const itutive 2-5A-dependent ribonuclease (RNase L) which upon activation by 2-5A , degrades RNA. This RNase I, enzyme can be recruited for antisense therape utics by linking it to an appropriate oligonucleotide targeted to a chosen RNA. Syntheses of 2-5A, its analogues, 2-5A-antisense, and its modification s are detailed herein. Applications of 2-5A-antisense to particular targets such as HIV, PKR, chronic myelogenous leukemia, telomerase, and respirator y syncytical virus are described.