Strategy for Development of Antiviral Agents

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We now recognize a considerable number of steps in the viral replication cycle that represent potential targets for selective attack. Any process that is more essential to the replication of the virus than to the survival of the cell is theoretically vulnerable. Examples include the following: (1) attachment of the virion to its cellular receptor followed by its entry and uncoating; (2) transcription by the viral transcriptase from the viral genome to produce viral rnRNA (or cDNA, in the case of the retroviruses); (3) regulation of the viral transcription program by viral regulatory genes; (4) translation of viral mRNA into protein; (5) posttranslational cleavage of proteins by virus-coded proteases; (6) replication of viral DNA or RNA by a virus-coded DNA polymerase or RNA-dependent RNA polymerase; (7) assembly/maturation of the virion. Table 16-1 provides examples of classes of antiviral agents known to target these key steps in the viral replication cycle. Many of the agents are still experimental, some still at the stage of laboratory investigation, and others are undergoing clinical trial.

A logical approach to the discovery of new antiviral chemotherapeutic agents is to isolate or synthesize substances that might be predicted to serve as a substrate or as an inhibitor of a known virus-coded enzyme, such as a transcriptase, replicase, or protease. A further refinement of this approach is well illustrated by the nucleoside analog acycloguanosine (acyclovir), an inhibitor of the herpesvirus DNA polymerase required for replication of viral DNA. Acyclovir is in fact an inactive prodrug which requires another

Table 16-1

Targets for Antiviral Chemotherapy

Table 16-1

Targets for Antiviral Chemotherapy

Process

Target

Agent

A t tach men t/ uncoa ting

Ligand on virion

Receptor analogs, disoxaril

Transcription of viral genome

Viral transcriptase

Transcriptase inhibitors,

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