Cordycepin analogues of 2-5A and its derivatives. Chemical synthesis and biological activity.

Cordycepin analogs of 2',5'-oligoadenylate inhibit human immunodeficiency virus infection via inhibition of reverse transcriptase

“…These data are in accordance with data obtained in a different assay system, using the rRNA cleavage assay (Wreschner et al, 1981). Previous data and the presented results demonstrate that the cordycepin analogues bind to RNase L but do not activate that enzyme (Sawai et al, 1983).…”

“…In contrast, 20 gM pCo3 was without any effect on RNase L activity; only the 28S and 18S rRNA bands were visible. These data confirm earlier observations (Sawai et al, 1983) which have been made by °The assay conditions are described under Materials and Methods; the standard assay systems were supplemented with 5-10 ^xg of enzyme protein w ith the exception of the experiments with disrupted ("disr") virions, for which 20 gg of viral protein was added; the incubation period was 60 min. The nature of templatc/primcr activated ("act.")…”

“…Evidence has been presented that the time period until onset of release of HIV-1 can be extended by interferon (which activates the 2-5A pathway) (Ho et al, 1985), antiviral compounds, e.g., 3'azido-3'-deoxythymidine (which causes a delay in the decrease in intracellular level of 2-5A) (Schroder et al, 1989), or mismatched dsRNA (e.g., Ampligen) (which activates the 2-5A synthetase) (Montefiori et al, 1987). Hence our groups and others (Sawai et al, 1983) work on strategies to control HIV infection by augmentation of the intracellular 2-5A pool in the following ways: (i) by synthesis of 2-5A analogues, e.g., phosphorothioate (Montefiori et al, 1989;Suhadolnik et al, 1989) or cordycepin derivatives (Montefiori et al, 1989;Sawai et al, 1983) which are more resistant against the 2-5A-degrading 2,,3'-exoribonuclease; (ii) by development of mismatched dsRNA with low cytotoxicity (Montefiori et al, 1987), which induces 2-5A synthetase; and (iii) by an "intracellular immunization approach" (Schroder et al, 1990).…”

“…The phosphorothioate and cordycepin analogues of 2-5A displayed antiviral activity in the micromolar concentration range. Surprisingly, the cordycepin analogues, which are known not to activate RNase L (Sawai et al, 1983), were reported to inhibit to some extent the HIV reverse transcriptase (RT) (Montefiori et al, 1989;Suhadolnik et al, 1989). In this paper we report that cordycepin analogues of the trimer of adenylic acid with 2',5'-phosphodiester linkages and a 5'-monophosphate (pA3) as well as its dephosphorylated core (A3) are potent inhibitors of HIV replication.…”

Replacement of the ribofuranose oxygen of 2-5A derivatives by methylene: synthesis of an aristeromycin analog of 2-5A core 5'-monophosphate (5'-O-phosphoryladenylyl)(2'.fwdarw.5')adenylyl(2'.fwdarw.5')adenosine 5'-monophosphate

“…That the ribose-phosphate backbone of the oligonucleotide must be an important recognition area for the endonuclease interaction is suggested by the relative inactivity of S'^'-linkage isomers such as pppS'AS'pS'AS'pS'A14 and cordycepin analogues such as ppp5/(3,dA)2'p5'(3/dA)2'p5' (3'dA). 10,11 To further extend this lead, we have prepared and evaluated the biological activity of a carbocyclic 2-5A analogue, that is, an analogue in which the ribofuranose oxygen of adenosine is replaced by methylene, giving the antibiotic aristeromycin.…”