Aciclovir selectivity and viral thymidine kinase
Aciclovir is switched on mainly in cells infected with herpes simplex or varicella zoster (chickenpox) virus, because only they make the viral enzyme thymidine kinase, which adds the first phosphate.
Remember
Aciclovir stays inactive until viral thymidine kinase adds the first phosphate group, so the active drug builds up mainly in infected cells.
Memory aid
A sleeper agent that does nothing until the virus's own thymidine kinase wakes it up
Aciclovir does nothing until the viral enzyme starts its activation.
Aciclovir is a guanosine analogue, a drug that closely resembles guanosine, one of the building blocks of DNA. It is also a prodrug, which means it is inactive until it is converted in the body. It is converted by phosphorylation, which means that phosphate groups are added to it one after another.
The first phosphate is added by viral thymidine kinase, an enzyme that adds phosphate groups and is made by herpes simplex virus (HSV) and by varicella zoster virus (VZV), the chickenpox virus that lies dormant in nerve cells and reactivates as shingles. Only infected cells have this enzyme. Human kinases then add two more phosphates, giving the active triphosphate form. Uninfected cells hardly activate the drug, so they are largely spared.
The active triphosphate is built into the viral DNA as it is copied. It acts as a chain terminator, because no further building blocks can be added, so viral DNA synthesis stops and replication halts.
This is the basis of its selective toxicity, which means harm to the virus with little harm to the patient's own cells. The virus supplies the key that switches the drug on, so the drug is active mainly where the virus is.
Key facts
- Drug type
- Aciclovir is a guanosine analogue and a prodrug, so it is inactive until phosphate groups are added.
- First step
- Viral thymidine kinase adds the first phosphate group, and it is present only in cells infected with HSV or VZV.
- Later steps
- Human kinases, which are enzymes that add phosphate groups, complete the active triphosphate form.
- Action
- The active triphosphate is built into viral DNA and terminates the chain, so viral replication halts.
- Uninfected cells
- They lack the viral enzyme, so they do not efficiently activate the drug and are largely spared.
- Ganciclovir
- In cytomegalovirus (CMV), ganciclovir is activated by the viral UL97 kinase rather than by thymidine kinase.
Exam traps
- Selectivity does not come from a host thymidine kinase working in every cell, because uninfected cells hardly activate the drug, so it stays largely inactive in them.
- Ganciclovir is also a nucleoside analogue (a false building block), but in cytomegalovirus (CMV) it is activated by the viral UL97 kinase rather than by thymidine kinase, and it is reserved for serious CMV disease in immunocompromised people (those with a weakened immune system), not shingles.
- Valaciclovir is the ester pro-drug of aciclovir (an inactive form that the body converts into the active drug), and it gives better absorption by mouth, but that is a separate point from selectivity, since aciclovir itself is activated by phosphorylation.
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