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

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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′ASH2′p5′ASH2′p5′ASH(pASH3) (1c) had little capacity to bind to RNase L. On the other hand, an analogue of the p5′AOH2′p5′AOH2′p5′AOH(pAOH3) (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, pASH3(1c) which possessed higher anti-HIV activity than pAg (1a) or pAOH3(1b).