4.11 Control of viral infections: antivirals

Question 1

What are the considerations for antiviral drugs?

Answer 1

• The best antiviral drugs inhibit a specific step in viral replication or pathogenesis but many of the viral replication steps also involve host proteins/processes
• Drug discovery can be accomplished by screening or rational design
• Emergence of virus mutants resistant to antiviral drugs is a serious problem
• Combination of targeted delivery strategies to control toxicities and resistance

Question 2

To what extent must an antiviral drug inhibit viral replication?

Answer 2

• A compound must block virus replication completely and must be potent
• Many standard pharmaceuticals can be effective if enzyme activity is partially blocked
• Partial inhibition is not acceptable for an antiviral drug

Question 3

What are the challenges for making antiviral drugs?

Answer 3

• Consequently, antiviral drug discovery is time consuming and expensive
• If a drug doesn’t block virus replication completely, resistant viruses will always emerge
• Viral replication in the presence of an inhibitor is a recipe for disaster: - evolution of resistant viruses will occur

Question 4

How do anti-influenza drugs function?

Answer 4

• Anti-influenza drugs: Zanamivir (Relenza) and Oseltamivir (Tamiflu)
• Inhibitors designed to mimic natural ligand, sialic acid affect the action of NA in cleaving sialic to release new infectious particles
• Closer inhibitor to natural compound, less likely target can change to avoid binding drug while maintaining viable function

Question 5

How can errors occur with anti-influenza drugs: Zanamivir and Oseltamivir?

Answer 5

• due to the error-prone nature of the viral RdRp mutations can frequently occur that confer resistance to antivirals - especially if the antivirals are excessively used

Question 6

What is the role of HIV protease in the production of infectious virions?

Answer 6

• It is present in the virion and becomes activated upon final assembly and exit of the virion
• It cleaves the Gag-Pol polyprotein into the final products:

• capsid, matrix, nucleocapsid, reverse transcriptase, integrase and protease.

Question 7

How do HIV protease inhibitors function?

Answer 7

• Blocking the function of the protease will stop the released virus from becoming infectious.
• They bind in the enzyme active site and block its activity.

Question 8

What is a current HIV treatment?

Answer 8

Question 9

What is the structure of antiviral drug acyclovir (nucleoside analogue)?

Answer 9

• Acyclovir is a guanosine analogue.
• Phosphate groups can be added so that the analogue can be incorporated into DNA
• But the 3’ hydroxyl group required to extend the DNA polymer is absent

Question 10

How does Acyclovir: nucleoside analogue funciton as an antiviral drug?

Answer 10

• Acyclovir is a prodrug: it must first be activated by the viral TK to subsequently be processed by cellular enzymes
• The final product Acyclovir-TP is incorporated into DNA and will cause chain termination and the infected cell will die