The Relationship between Conformation and Biological Activity of 8-substituted Analogues of 2′,5′-Oligoadenylates

Abstract

Analogues of the 2′,5′-linked adenylate trimer 5′-monophosphates, p5′A2′p5′A2′p5′A (pA₃) (1a), containing 8-hydroxyadenosine and 8-mercaptoadenosine in the first, second, and third nucleotide positions were tested for their ability to bind to and activate RNase L of mouse L cells. The oligomer, p5′A^SH2′p5′A^SH2′p5′A^SH (pA^SH₃) (1c) had little capacity to bind to RNase L. On the other hand, an analogue of the p5′A^OH2′p5′A^OH2′p5′A^OH (pA^OH₃) (1b) bound almost as well as the parent 2-5A [pppA(2′p5′A)₂] (P₃A₃) (1d) to RNase L. The 8-substituted analogues of 2-5A were more resistant to degradation by (2′,5′) phosphodiesterase. Finally, the monophosphate, pA^SH₃ (1c) which possessed higher anti-HIV activity than pAg (1a) or pA^OH₃ (1b).