THE PROBLEM

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THE PROBLEM

• Antiviral drugs must inhibit virus replication
• BUT
• viruses depend on host metabolic pathways

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THE SOLUTION

• Inhibit virus encoded proteins
• with essential functions
• BUT
• must be specific

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• THERAPEUTIC INDEX
• Minimum virus inhibitory dose
• Minimum cell toxic dose
• Should be at least 10 preferably 102-103

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THERAPEUTIC STRATEGIES

• Inhibit virus replication at-
• Attachment
• Penetration/Uncoating
• Nucleic acid synthesis
• Assembly
• Maturation
• Release

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NUCLEIC ACID SYNTHESIS

• Viral DNA polymerase
• Viral Reverse Transcriptase (RT)
• Inhibited by nucleoside analogues

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INHIBITION of VIRAL DNA POLYMERASE

• ACYCLOVIR/ACICLOVIR for
• Herpes simplex virus (HSV)
• Varicella zoster virus (VZV)

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• ACYCLOVIR (ACV) - MODE of ACTION
• HSV VZV thymidine kinase? ACV-P
• ACV-P ? ACV-PPP by cell
• ACV-PPP inhibits viral DNA polymerase
• Herpes simplex virus
• Varicella zoster virus

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Acyclovir mechanism of action
nucleosides
Nuc-P
Nuc-P
Nuc-3P
Nuc-3P
HSV DNA polymerase
Herpesvirus-infected cell
Uninfected cell
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• RESISTANCE TO ACYCLOVIR
• Common Virus TK absent
• or
• altered substrate specificity
• Rarely Virus DNA polymerase
• altered substrate specificity
• Thymidine kinase

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Drugs to bypass phosphorylation

• ACV
• ? Viral thymidine kinase
• ACV-P
• ? cellular kinases
• ACV- PPP
• ? viral DNA polymerase ? Foscarnet
• Viral DNA

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RETROVIRUSES eg HIV

• RT synthesises DNA from HIV RNA genome
• RT inhibitors
• Nucleoside
• e.g. AZT (azidothymidine aka zidovudine)
• Non-nucleoside
• e.g. nevirapine
• Reverse transcriptase

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AZT
ACV
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Acyclovir v Zidovudine (AZT)

• AZT
• ? Cellular kinases
• AZT-P
• ? cellular kinases
• AZT- PPP
• ? viral RT
• Viral DNA
• ?
• Chain termination

• ACV
• ? Viral thymidine kinase
• ACV-P
• ? cellular kinases
• ACV- PPP
• ? viral DNA polymerase
• Viral DNA
• ?
• Chain termination

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NON-NUCLEOSIDE RT INHIBITORS

• Act by allosteric inhibition
• eg nevirapine

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THERAPEUTIC STRATEGIES

• Inhibit virus replication at-
• Attachment
• Penetration/Uncoating
• Nucleic acid synthesis
• Assembly
• Maturation
• Release

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INHIBIT VIRUS PROTEASE TO INHIBIT VIRUS MATURATION
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• DETERMINANTS of VIRAL RESISTANCE
• Increased mutation rate
• high virus replication
• immunosuppression
• RNA v DNA virus
• Selection pressure
• potent drug
• lengthy treatment
• BUT
• No resistance if virus fully suppressed

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• HIV - PROBLEMS WITH HAART
• Expensive
• Compliance
• Cant eradicate latent virus
• Viral load rebounds if stopped
• Drug resistance
• (RT no proof reading)

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THERAPEUTIC STRATEGIES

• Inhibit virus replication at-
• Attachment
• Penetration or fusion/Uncoating
• Nucleic acid synthesis
• Assembly
• Maturation
• Release

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T20 Binds to GP41 and Inhibits HIV Entry
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THERAPEUTIC STRATEGIES

• Inhibit virus replication at-
• Attachment
• Penetration or fusion/Uncoating
• Nucleic acid synthesis
• Assembly
• Maturation
• Release

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6.2.13
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In endosome low pH activates M2 ion
channel Protons enter virus Uncoating of viral
nucleic acid proceeds
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Amantadine blocks M2 prevents uncoating
Amantadine
Influenza virus envelope
M2 ion channel protein
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6.2.17
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THERAPEUTIC STRATEGIES

• Inhibit virus replication at-
• Attachment
• Penetration/Uncoating
• Nucleic acid synthesis
• Assembly
• Maturation
• Release

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NA inhibitor
6.2.19
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Influenza virus attachment

• Haemagglutinin (virus attachment protein)
• binds to
• sialic acid on cell surface
• (cell receptor)

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Release of Influenza Virus

• Virus trapped on cell surface since
  haemagglutinin binds sialic acid
• Neuraminidase aids release
• Neuraminidase inhibitors block release

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• ANTIVIRAL THERAPY
• Difficult since viruses are intracellular
• Latent viruses cannot be eradicated

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INHIBIT VIRUS REPLICATION AT

• Fusion - HIV about to be licensed
• Uncoating amantadine for influenza
• Nucleic acid synthesis
• - nucleoside analogues
• - other e.g. foscarnet nevirapine
• Maturation - HIV protease inhibitors
• Release - Neuraminidase inhibitors