Synthesis of 2′,5′-oligoadenylate analogs containing an adenine acyclonucleoside and their ability to activate human RNase L

This paper described synthesis of 2′,5′-oligoadenylate (2–5A) analogs containing the purine acyclonucleoside, 9-[(2′S,3′R)-2′,3′,4′-trihydroxybutyl]adenine (2). The ability of the analogs to activate recombinant human RNase L was evaluated using 5′-32P-r(C11U2C7)-3′ as a substrate. The EC50 value (the concentration of the 2–5A required to cleave half of the RNA) of the parent 2–5A tetramer 13 was 1.0 nM, whereas those of the analog 14 incorporating 2 at the second position from the 5′-end and the analog 15 incorporating 2 at the third position from the 5′-end were 9.0 and 1.7 nM, respectively. The analogs 14 and 15 were only 9- and 1.7-fold less potent than the parent 2–5A 13 itself, in RNase L activation ability. Furthermore, the oligodeoxynucleotide containing 2 was more resistant to nucleolytic hydrolysis by snake venom phosphodiesterase (a 3′-exonuclease) than the unmodified oligodeoxynucleotide. Thus, incorporation of an acyclonucleoside into 2–5A may be useful for developing an antiviral agent based on the 2–5A system.