Treatment of viral disease

Question 1

Why is it difficult to develop drugs that selectively act against viral infections?

Answer 1

Viruses use host’s machinery so therapies could be detrimental to the host as well as the virus
High selectivity is needed in order to interfere with the virus but not the host

Question 2

What is the general strategy for rational drug design?

Answer 2

1) Identify elements of viral life cycle that differ from host’s
2) Identify site of drug action
3) Design the drug to be highly specific for the site
4) Block spread/replication/dissemination of virus

Question 3

What stages of the viral life cycle could allow therapeutic intervention and why?

Answer 3

1) Binding and entry - virus requires specific cell receptors/binding site so if this is modified virion cannot enter cell
2) Replication - Encoding of its own enzymes can be targeted, or reverse transcription could be blocked
3) Assembly
4) Exit - some need to be cleaved by enzymes for release from host cell

Question 4

What are 6 examples of classes of drugs that have been successfully used in antiviral therapy?

Answer 4

Interferons
Nucleoside analogues
Fusion/entry inhibitors
Non-nucleoside reverse transcriptase inhibitors
Integrase inhibitors
Protease inhibitors

Question 5

Explain the specific strategy of acyclovir/nucleoside analogues

Answer 5

Acyclovir acts on viral thymidine kinase
Has a high affinity for acyclovir→converts it to acycloGMP→generates acycloGTP
AcycloGTP good substrate for viral DNA polymerase→incorporates it into growing viral DNA→AcycloGTP blocks further polymerisation as it has no 3’ OH group
AcycloGTP poor substrate for HOST cell DNA polymerase