Early-acting benzimidazole and pyrrolo[2,3-<italic>d</italic>]pyrimidine inhibitors of human cytomegalovirus.
Evers, David Lawrence
2002
Abstract
Two chemically distinct series of nucleoside analogs that inhibit human cytomegalovirus (HCMV) early in its replication cycle have been discovered in the laboratories of professors Leroy B. Townsend and John C. Drach. I have investigated the virological and biochemical basis by which these pyrrolo[2,3-<italic> d</italic>]pyrimidines and benzimidazole nucleosides act against HCMV. I have established that a more potent next generation of pyrrolo[2,3-<italic>d</italic>]-pyrimidine nucleoside analogs is similar to parent compounds in biological activity and mode of action. Like prior members of this series, newer compounds act early in the viral replication cycle and display multiplicity of infection (MOI) dependence. Similarly, I have been unable to select and isolate pyrrolo[2,3-<italic>d</italic>]pyrimidine-resistant HCMV. Consequently, we hypothesized that pyrrolo[2,3-<italic>d</italic>]pyrimidines may exert their antiviral effects via the inhibition of cellular cyclin-dependent kinases (cdk's). The evaluation of this hypothesis led to the conclusion that pyrrolo[2,3-<italic>d</italic>]pyrimidines define a pharmacophore with potencies against cdk1/cyclin B ranging from moderate to no inhibition. One compound in this series (UMJD 1369) with a potency against a cdk similar to that of control purine analog roscovitine, was shown to inhibit the kinase as a competitive inhibitor with respect to ATP. Our data also indicated that literature reports of roscovitine's antiviral activity were most likely artifacts of cellular cytotoxicity. Previously studied benzimidazole nucleosides act late in the HCMV replication cycle by the inhibition of viral DNA synthesis or viral DNA processing. I have discovered that certain other benzimidazole nucleosides have a third early mode of antiviral action against HCMV. To the best of our knowledge, this is the first report of a closely related series of antiviral compounds that has three distinct modes of action against one virus. HCMV resistant to two classes of late-acting benzimidazoles were sensitive to certain structurally similar benzimidazoles (such as UMJD 1311). Benzimidazoles like 1311 possess antiviral biological properties similar to those determined for pyrrolo[2,3-<italic> d</italic>]pyrimidines. They act early in the viral replication cycle and display multiplicity of infection (MOI) dependence. Similarly, I have been unable to select and isolate early-acting benzimidazole-resistant HCMV. Thus the antiviral biology of two seemingly distant classes of compounds converged upon a similar mode of antiviral action. In further studies, I have shown that the MOI dependence of pyrrolo[2,3-<italic>d</italic>]pyrimidines and early-acting benzimidazoles requires an intact viral genome, and that the antiviral effect(s) of these compounds appears to be independent of the major immediate early antigen of HCMV. These studies have significantly narrowed the potential hypotheses to explain the biochemical mode of action by which pyrrolo[2,3-<italic>d</italic>]pyrimidine nucleoside analogs and certain benzimidazole nucleosides inhibit HCMV.Subjects
Acting Antiviral Benzimidazole Cytomegalovirus Early Human Inhibitors Pyrrolo[2,3-d]pyrimidine
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