A. The Chemistry of Antiviral Compounds

There are few restrictions on the types of molecules that inhibit virus replication, at least in the laboratory. They vary greatly in complexity and include natural products of plants, synthetic oligonucleotides, oligosaccharides, simple inorganic and organic compounds and nucleoside analogues. Examples of antiviral compounds in current use include:

1. Nucleoside analogues - thousands of analogues of naturally occurring nucleosides have now been synthesized and tested in the laboratory, initially as herpesvirus inhibitors and many now are retested as anti-HIV agents. In addition to purine and pyrimidine nucleosides, ara-, amino, aza-nucleosides or nucleotides have been synthesized. Even single atomic substitution may change an active to an inactive molecule.
2. Pyrophosphate analogues - forscarnet is an example of a pyrophosphate analogue. This specifically inhibits herpesvirus DNA polymerase at the pyrophosphate binding sites and it also has anti-HIV activity.
3. Amantidine molecules - amantidine is licensed for the treatment of influenza A infection. Addition of a methyl grouping (rimantidine) alters the pharmacological distribution of the drug and prevents entry to the brain, thus reducing the side effect described as "jitteriness"

 The search for new antiviral compounds

All the antiviral drugs now known were discovered by random search in the laboratory. With developments in molecular biology and the advent of HIV, more attention is now being paid to the development of drugs designed to act on specific targets on the virus itself or in its replication. Attempts are being made to exploit data on viral nucleic acid sequences, X-ray crystallographic studies of viral proteins and enzymes. A recent example of the success of this new rational approach has been the discovery of potent neuraminidase inhibitors of influenza viruses.

Resistance of viruses to inhibitors

A disappointing feature of antiviral chemotherapy has been the failure so far of any antiviral molecule to inhibit virus replication completely. Antiviral activity tends to produce a 100 to 1000 fold reduction in virus titre which, although significant, still allows some infective particles to survive. This may have important consequences in immunocompromized patients who may be unable to eradicate any residual virus. It is not known for certain whether these virions are drug-resistant mutants or with different biologically or genetically from the major portions of the virus population.