2′–5′-Oligoadenylates (2–5A) As Mediators of Interferon Action. Synthesis and Biological Activity of New 2–5A Analogues

Abstract

Double-stranded RNA (dsRNA) is a potent inhibitor of protein synthesis in extracts of interferon-treated cells. One of the mechanisms that has been proposed to explain this inhibition of protein synthesis is by the 2–5A pathway (1). Interferon induces the synthesis of an enzyme, 2–5A synthetase, which upon activation by dsRNA generates 2–5A from ATP. This 2–5A activates a pre-existing endonuclease for cleavage of single-stranded RNA. The biological activity of 2–5A is rapidly lost due to cleavage of the 2′–5′ internucleotide bond by a specific 2′–5′ phosphodiesterase starting at the 3′-end. This rapid cleavage and the poor uptake of 2–5A in intact cells, the latter because of its ionic character, limit the potential of 2–5A as a useful approach to the treatment of virus infections or cancer.