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' leads to 5' phosphodiester bond, commonly abbreviated as 2-5A, are synthesized in interferon-treated virally-infected cells and have been implicated in several systems as contributing to interferon's antiviral activity. The 2-5A binds to and subsequently activates an endogenous endonuclease, ultimately resulting in degradation of RNA. 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) 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 and 3T3 fibroblasts, Williams and Kerr have reported lack of antiviral activity against Semliki Forest virus or encephalomyocarditis virus by exogenously-administered 2-5A core. 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 species. 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.

Increased stability and antiviral activity of 2′‐O‐phosphoglyceryl derivatives of (2′‐5′)oligo(adenylate)

“…This latter, however, has been assessed by inhibition of macromolecular synthesis or activation of RNase L, only. On the other hand, core anglogues [11,12] and in particular (2'-5')oligo(xylosyladenine) derivatives [I21 have been described as having an increased antiviral activity which is, however, restricted to DNA viruses. In our hands, even stable 0-phosphoglyceryl derivatives of (2'-5')(A), cores d c not exhibit any antiviral activity against RNA viruses.…”

C-nucleoside studies. Part 19. The synthesis of the β-D-xylofuranosyl analogue of formycin

“…Oxidation" of the alcohol (6) gave the ketone (10). and it had previously been demonstrated that hydride reduction of this ketone gave stereoselectively the D-ido-isomer (1 I).'…”

pppA2'p5A' blocks vesicular stomatitis virus replication in intact cells

“…DISCUSSION Despite the attention attracted by the use of 2'5'A as a direct antiviral agent, little success has been obtained because of its incapacity to penetrate animal cells (24,26). However, some of its analogs have been effective against several DNA virus (7,8,13). 2'5'A, itself, also has an effect against Rous sarcoma virus (2) and tobacco mosaic virus (6), but in none of these instances was it possible to demonstrate that the basis for the antiviral effect is mediated by the activation of RNase F. Our findings that pppA2'p5'A has an effect against VSV are in agreement with those results showing that some of these compounds might directly block viral replication.…”