Zidovudine - Mechanism of Action

Mechanism of Action

AZT works by selectively inhibiting HIV's reverse transcriptase, the enzyme that the virus uses to make a DNA copy of its RNA. Reverse transcription is necessary for production of HIV's double-stranded DNA, which would be subsequently integrated into the genetic material of the infected cell (where it is called a provirus).

The azido group increases the lipophilic nature of AZT, allowing it to cross infected cell membranes easily by diffusion and thereby also to cross the blood–brain barrier. Cellular enzymes convert AZT into the effective 5'-triphosphate form. Studies have proven that the termination of HIV's forming DNA chains is the specific factor in the inhibitory effect.

At very high doses, AZT's triphosphate form may also inhibit DNA polymerase used by human cells to undergo cell division, but regardless of dosage AZT has an approximately 100-fold greater affinity for HIV's reverse transcriptase. The selectivity has been proven to be due to the cell's ability to quickly repair its own DNA chain if it is broken by AZT during its formation, whereas the HIV virus lacks that ability. Thus AZT inhibits HIV replication without affecting the function of uninfected cells. At sufficiently high dosages, AZT begins to inhibit the cellular DNA polymerase used by mitochondria to replicate, accounting for its potentially toxic but reversible effects on cardiac and skeletal muscles, causing myositis.

AZT's therapeutic mechanism is unrelated to chemotherapy and cannot negatively impact the immune system.