Xyloadenosine analogue of (A2′p)₂A inhibits replication of herpes simplex viruses 1 and 2

Abstract

Molecules of the structure ppp(A2′p)₂A containing a 2′→5′ phosphodiester bond, commonly abbreviated as 2-5A, are synthesized in interferon-treated virally-infected cells¹ and have been implicated in several systems as contributing to interferon's antiviral activity^2–7. The 2-5A binds to and subsequently activates an endogenous endonuclease, ultimately resulting in degradation of RNA ^3–5,8–10. We have been interested in the use of 2-5A analogues to achieve antiviral activity without the use of interferon. For this approach to be successful, analogues must be synthesized with an increased stability (native 2-5A is rapidly degraded by cellular phosphodiesterases^11–14) and with increased ability to enter intact cells. Removal of the highly-negative charged 5′ terminal phosphates from ppp(A2′p)₂A results in formation of the ‘core’ species, (A2′p)₂A, which should be able to penetrate intact cells more readily. While Kimchi et al. have shown that 2-5A core has an antimitogenic effect in mouse spleen lymphocytes^15,16 and 3T3 fibroblasts¹⁷, Williams and Kerr have reported lack of antiviral activity against Semliki Forest virus or encephalomyocarditis virus by exogenously-administered 2-5A core³. We have previously determined that (xyloA2′p)₂xyloA (abbreviated as xylo 2-5A core), the xyloadenosine analogue of the 5′-terminally dephosphorylated 2-5A core, is over 100 times more stable than the parent 2-5A core species¹⁸. We now report that this xylo 2-5A core inhibits replication of herpes simplex viruses 1 and 2 in vitro, with greater than 100 times the activity of the parent 2-5A core. The mechanism of antiviral action of the 2-5A core analogue appears to involve a pathway different from that activated by the parent 5′ triphosphorylated 2-5A species.