ANTIVIRAL AGENTS

There are relatively few drugs that are active against viruses and their effectiveness is often restricted to preventive or disease-limitation treatment. However, some antivirals can be life-savers, especially in immunocompromised patients. Infections due to the herpes viruses (e.g. cold sores, genital herpes, shingles and chickenpox) may be prevented or contained by early treatment with acyclovir. Serious cytomegaloviral infections may also be contained by treatment with ganciclovir. There are now some HIV treatments that are moderately effective against the virus itself that are used in treating AIDS, these include zidovudine. Problems special to HIV-1 are dealt with under another heading, ANTI-HIV AGENTS.

Which antiviral drugs work or how the disease is dealt with in terms of public health measures, depends, in part, on the type of virus. The DNA viruses are relatively stable in form since mutations are internally corrected, and here it is often more effective to use vaccination than chemotherapy. By these means smallpox has been eradicated. For some RNA viruses, vaccination is also effective, including poliomyelitis, rubella, measles and mumps, and some rabies strains. Other viruses mutate so rapidly that vaccination is more difficult, e.g. influenza, the common cold, HIV.

Mechanisms of action In principle, antivirals can act at various stages of the viral replication process, though by no means have all possible mechanisms yet been exploited in terms of finding effective drugs acting in that way. Some of these stages are as follows.

(1) Inhibition of attachment to, or penetration of, the host cell by the virus. Viruses use various cell structures for attachment, for instance, AIDS virus to the CD4 molecule on the T lymphocytes, or the rabies virus to the nicotinic cholinoceptor. Amantadine inhibits uncoating and is effective against influenza A virus, which is an RNA virus, though is not active against influenza B virus. It has a high success rate when used prophylactically. In a different manner, gamma globulin can be used to give passive immunity against a number of viruses, by neutralizing them so they cannot attach (though there may be other actions). In the case of HIV, where the virus binds to the CD4 molecule on the T lymphocytes, binding might be inhibited with soluble recombinant CD4 (sCD4) or competitive CD4 receptor peptides. Further, toxins (e.g. Pseudomonas toxin) may be attached to CD4 as a delivery system. Several of these approaches are under investigation.

(2) Inhibition of nucleic acid synthesis. REVERSE TRANSCRIPTASE INHIBITORS are used in the treatment of retroviral infections, including AIDS. In RNA retroviruses (e.g. AIDS and T-cell leukaemia), the virion contains a reverse transcriptase enzyme that makes a DNA copy of the viral RNA, and this copy is incorporated into the host genome, and is termed a provirus. The proviral DNA is transcribed into new genomic RNA, and mRNA for translation into viral proteins. Such viruses replicate by a budding process, which does not kill the host cell. In the treatment of AIDS, a number of drugs are being, or have been developed that act at this stage, including zidovudine, didanosine and zalcitabine. Some others that work somewhat differently are foscarnet sodium, nevirapine, carbovir and TIBO analogues.

(3) Integration of viral DNA into the host genome, or transcription of viral mRNA into viral proteins by host ribosomes are specific processes that may, in principle, be inhibited. Antisense oligonucleotides offer the required selectivity, and are under investigation.

(4) Translation of viral mRNA into viral proteins by host ribosome can be affected by myristic acid analogues.

(5) Interference with assembly of viral coat proteins and viral RNA into new virus particles. Interferons may induce in the ribosomes of the host cells production of enzymes that inhibit translation of viral proteins. Avarol and avarine are thought to interfere with cytoskeletal assembly of virus particles. PROTEASE INHIBITORS can prevent the release of reverse transcriptase, and HIV-1 proteinase (e.g. saquinavir) are under development or in trial application.

(6) Interfering with release of new virus particles by budding from the host cell. This may be inhibited by interferons.

Hence, there are many steps that can, in principle, be manipulated in the treatment of viral diseases.