Question

The genome of herpes-type viruses is linear double-stranded DNA. Acyclovir is an agent
antiviral that inhibits DNA replication in cells infected by this virus. It is administered to
patients in dephosphorylated form although it acts only after it is modified by
phosphorylation. 

a) Propose a possible mechanism of inhibition of replication.
b) Acyclovir has very few side effects because it is only modified in cells
infected. Explain.
c) Herpes virus can become insensitive to acyclovir therapy by mutations in two
genes. Discuss what those genes might be.

Answer 1

a) Propose a possible mechanism of inhibition of replication.

  Acyclovir, are nucleoside analogues that lacks free 3' group. In DNA replication, new nucleosides are added to the 3'end of replicating chain. Acyclovir triphosphate will bind with the replicating viral gene and further nucleotide addition will completely prevents. Also it competitively inhibits viral DNA polymerase. DNA polymerase is the major enzyme for the synthesis of DNA. Thereby replication of viral DNA inhibited.

b). Acyclovir has very few side effects because it is only modified in cells infected. Explain. 

Acyclovir is administrated by the patients in dephosphorylated form (Inactive form). It activates only after the phosphorylation. Inside the virus, a specialized protein thymidine kinase (TK), which phophorylate acyclovir to Acyclovir triphosphate. So this medicine is only activated inside the virus infected cell. The rest of the cells are free from the activation of Acyclovir and its side effects.

c) Herpes virus can become insensitive to acyclovir therapy by mutations in two genes. Discuss what those genes might be.?

Acyclovir is activated by the gene product thymidine kinase through phosphorylation. So if the gene which codes for thymidine kinase is mutated, the virus can resist acyclovir.

Acyclovir competitively inhibits the action of DNA polymerase also. Alteration (Mutation) in the genes codes for DNA polymerase also results viral insensitivity to Acyclovir. DNA polymerase is the major enzyme needed for DNA replication. So the mutation never stop the DNA polymerase activity in the virus which is insensitive to Acyclovir. Do not alter the function but change the shape.