Antimicrobials (2): Antivirals

Submitted by amh10 on 29 October, 2006 - 11:38
  • Antiviral agents should be given immediatley after infection or clinical signs of infection.
  • Prophylactic use occasionally.
  • Any of the stages of viral replication can be a target for antiviral intervention.
  • The only requirements are:
    • That the process targeted be essential for virus replication.
    • That the theraputic agent is active against the virus while having "acceptable toxicity" to the host organism.
Drug: Viruses: Chemical Type: Target:
Vidarabine Herpesviruses Nucleoside analogue Virus polymerase
Acyclovir Herpes simplex (HSV) Nucleoside analogue Virus polymerase
Gancyclovir and Valcyte ™ (valganciclovir) Cytomegalovirus (CMV) Nucleoside analogue Virus polymerase (needs virus UL98 kinase for activation)
Nucleoside-analog reverse transcriptase inhibitors (NRTI): AZT (Zidovudine), ddI (Didanosine), ddC (Zalcitabine), d4T (Stavudine), 3TC (Lamivudine) Retroviruses (HIV) Nucleoside analogue Reverse transcriptase
Non-nucleoside reverse transcriptase inhibitors (NNRTI): Nevirapine, Delavirdine Retroviruses (HIV) Nucleoside analogue Reverse transcriptase
Protease Inhibitors: Saquinavir, Ritonavir, Indinavir, Nelfinavir HIV Peptide analogue HIV protease
Ribavirin Broad spectrum: HCV, HSV, measles, mumps, Lassa fever Triazole carboxamide RNA mutagen
Amantadine / Rimantadine Influenza A strains Tricyclic amine Matrix protein / haemagglutinin
Relenza and Tamiflu Influenza strains A and B Neuraminic acid mimetic Neuraminidase Inhibitor
Pleconaril Picornaviruses Small cyclic Blocks attachment and uncoating
Interferons Hepatitis B and C Protein Cell defense proteins activated


This phase of replication can be inhibited in two ways:

a) Using agents which mimic the V.A.P. and bind to the cellular receptor, e.g:

  • anti-receptor antibodies
  • V.A.P. anti-idiotypic antibodies
  • natural ligands of the receptor, e.g. epidermal growth factor/Vaccinia virus
  • synthetic ligands, e.g. synthetic peptides resembling the receptor-binding domain of the V.A.P. itself.

b) Agents which mimic the receptor and bind to the V.A.P:

  • anti-V.A.P. antibodies (a natural component of the antibody response to virus infection/vaccination)
  • receptor anti-idiotypic antibodies
  • extraneous receptor, e.g. rsCD4/HIV
  • synthetic receptor mimics, e.g. sialic acid derivatives/influenza virus.

Penetration / Uncoating

It is difficult to specifically target these stages of the life cycle as relatively little is known about them. Uncoating in particular is largely mediated by cellular enzymes, although like penetration, is often influenced by one or more virus proteins.

Pleconaril is a broad spectrum anti-picorna virus agent. It is orally bioavailable and reduces peak viral titres by more than 99%; symptoms are improved. It is a small cyclic drug which binds to a canyon pore of the virus. In doing so it blocks attachment and uncoating of the viral particle

Amantadine and rimantadine are active against influenza A viruses. The action of these closely related agents is complex and incompletely understood, but they are believed to block cellular membrane ion channels.

  • The target for both drugs is the matrix protein (M2).
  • Drug-treated cells are unable to lower the pH of the endosomal compartment (a function normally controlled by the M2 gene product), a process which is essential to induce conformational changes in the HA protein to permit membrane fusion.

Genome Replication

Many viruses have evolved their own specific enzymatic mechanisms to preferentially replicate virus nucleic acids at the expense of cellular molecules. There is often sufficient specificity in virus polymerases to provide a target for a specific antiviral agent, and this method has produced the majority of the specific antiviral drugs currently in use.
The majority of these drugs function as polymerase substrate (i.e. nucleoside/nucleotide) analogues. The toxicity of these drugs varies considerably from some which are well tolerated (e.g. acyclovir) to others which are highly toxic (e.g. IdU/TFT/AZT). There is a serious problem with the pharmacokinetics of these nucleoside analogues, e.g. typically short serum half lives of 1-4h.

Nucleoside analogues are in fact pro-drugs, since they need to be phosphorylated before becoming effective. This is the key to their selectivity:

  • Acyclovir is phosphorylated by HSV tk 200 times more efficiently than by cellular enzymes. The cell DNA polymerase is less sensitive to it than the viral DNA polymerase.
  • Gancyclovir is 10 times more effective against CMV than acyclovir since it is specifically phosphorylated by a CMV-encoded kinase encoded by gene UL97.

Therapy of HIV Infection:

Several distinct classes of drugs are now used to treat HIV infection:
  1. Nucleoside-Analog Reverse Transcriptase Inhibitors (NRTI). These drugs inhibit viral RNA-dependent DNA polymerase (reverse transcriptase) and are incorporated into viral DNA (they are chain-terminating drugs).
    • Zidovudine (AZT = ZDV, Retrovir) first approved in 1987
    • Didanosine (ddI, Videx)
    • Zalcitabine (ddC, Hivid)
    • Stavudine (d4T, Zerit)
    • Lamivudine (3TC, Epivir)
  2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). In contrast to NRTIs, NNRTIs are not incorporated into viral DNA; they inhibit HIV replication directly by binding non-competitively to reverse transcriptase.
    • Nevirapine (Viramune)
    • Delavirdine (Rescriptor)
  3. Protease Inhibitors. These drugs are specific for the HIV-1 protease and competitively inhibit the enzyme, preventing the maturation of virions capable of infecting other cells.
    • Saquinavir (Invirase) first approved in 1995
    • Ritonavir (Norvir)
    • Indinavir (Crixivan)
    • Nelfinavir (Viracept)

Source: MSB@le.ac.uk

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