Acyclovir exerts its antiviral activity primarily through inhibition of which viral enzyme?

Explanation

## Mechanism of Acyclovir Action **Key Point:** Acyclovir is a nucleoside analogue that requires viral thymidine kinase (TK) for phosphorylation to its active triphosphate form, which then inhibits viral DNA polymerase. ### Activation Pathway 1. Acyclovir enters the cell 2. Viral thymidine kinase phosphorylates acyclovir → acyclovir monophosphate 3. Cellular enzymes further phosphorylate → acyclovir triphosphate (active form) 4. Acyclovir triphosphate inhibits viral DNA polymerase competitively 5. Causes chain termination (lacks 3'-OH group) **High-Yield:** The requirement for viral TK is why acyclovir is selective for herpes simplex virus (HSV) and varicella-zoster virus (VZV) — these viruses encode their own TK. Cytomegalovirus (CMV) is relatively resistant because it has low or absent TK activity, requiring ganciclovir instead. **Clinical Pearl:** Acyclovir-resistant HSV mutants typically arise from TK deficiency or altered viral DNA polymerase, not from primary resistance mechanisms seen with other antivirals. ### Target Enzyme Specificity | Antiviral | Target Enzyme | Virus | Mechanism | | --- | --- | --- | --- | | Acyclovir | Viral DNA polymerase | HSV, VZV | Chain terminator | | Ganciclovir | Viral DNA polymerase | CMV, HSV | Chain terminator (more potent) | | Foscarnet | Viral DNA polymerase | CMV, HSV, VZV | Pyrophosphate analogue | | Ribavirin | Viral RNA polymerase | RSV, HCV, measles | Nucleoside analogue | **Mnemonic:** **ACYCLO** = **A**ctive against **C**ytomegalovirus? **NO** (needs ganciclovir). **A**ctive against **HSV/VZV**? **YES**.