Antiviral Drugs (Non-retroviral)

Antiviral Drugs (Non-retroviral)

1. Definition, principles & general challenges of antiviral chemotherapy

• Viruses are obligate intracellular parasites — they not only take nutrition from the host cell but also redirect its metabolic machinery to synthesise new virus particles; thus early workers thought viral chemotherapy impossible, as it seemed to demand interference with host cellular metabolism (KDT 8e Ch.59, p.849).
• Selective antiviral toxicity became feasible because virus-directed enzymes (distinct from host enzymes) were identified in infected cells, and some viruses carry their own enzymes with higher affinity for certain antimetabolites/inhibitors than the corresponding cellular enzymes (KDT 8e Ch.59, p.849).
• Effective agents either block viral entry/exit from the cell or are active inside the host cell; non-selective inhibitors of replication interfere with host-cell function and cause toxicity (Katzung Ch.49, p.910).
• Antiviral drugs share the common property of being virustatic — active only against replicating virus and not against latent virus (Katzung Ch.49, p.910).
• A key clinical obstacle: in most acute infections viral replication is already at peak when symptoms appear, so therapy must be started in the incubation period — i.e. prophylactic or pre-emptive — to be maximally effective (KDT 8e Ch.59, p.849).
• The field was driven by the discovery/development of acyclovir (Elion, 1986) — Gertrude Elion & George Hitchings shared the 1988 Nobel Prize in Physiology/Medicine (with James Black) "for their discoveries of important principles for drug treatment" (G&G 14e Ch.62, p.1211).
• Stages of viral replication amenable to drug attack (each has a class of selective inhibitor) (G&G 14e Ch.62, Table 62–1, p.1212):
  • Cell entry — attachment/penetration → soluble receptor decoys, antireceptor antibodies, fusion-protein inhibitors.
  • Uncoating (release of viral genome) → ion-channel blockers (adamantanes), capsid stabilisers.
  • Transcription/genome replication → inhibitors of viral DNA polymerase, RNA polymerase, reverse transcriptase, helicase, primase, integrase.
  • Translation of viral proteins → interferons, antisense oligonucleotides, ribozymes.
  • Post-translational modification (proteolytic cleavage) → protease inhibitors.
  • Assembly → interferons, assembly inhibitors.
  • Release (budding/lysis) → neuraminidase inhibitors, antiviral antibodies.

Virus structure & replication strategy (drug-target context)

• DNA viruses (poxvirus, herpesvirus, adenovirus, hepadnavirus/HBV, papillomavirus): most enter the host nucleus where viral DNA is transcribed to mRNA by host polymerase; poxviruses are an exception — they carry their own RNA polymerase and replicate in cytoplasm (G&G 14e Ch.62, p.1211).
• RNA viruses (orthomyxovirus/influenza, paramyxovirus, flavivirus/HCV-Zika, picornavirus, coronavirus, etc.): replication relies on virion enzymes to make mRNA or uses viral RNA as its own mRNA; most replicate in cytoplasm, but influenza is transcribed in the nucleus (G&G 14e Ch.62, p.1211).
• Retroviruses (HIV) are RNA viruses covered separately (G&G Ch.64) — explicitly out of scope for this non-retroviral topic (G&G 14e Ch.62, p.1211).