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AZT's Mechanism of Antiviral Activity

This animation shows the chemical details of how the antiviral drug AZT acts as a chain terminator in replicating DNA. The term "chain terminator" is a difficult concept to explain to those students who do not have a good grasp of nucleic acid chemistry. It is important to understand the exact mechanisms of DNA replication at the atomic resolution level as a prerequisite for understanding AZT action. This animation helps the students to visualize the whole chemical process of chain termination. This animation consists of four small segments and shows how a normal strand of DNA unravels in preparation for replication. In the next part of the animation, two base pairs are added to a growing DNA strand. Worth noting here is the fact that each new base pair is attacked by the 3'-OH on the existing DNA strand. This OH group attacks the incoming base pair's a-phosphate group, leading to the formation of a bond between the incoming base pair and the growing DNA strand while causing the release of a diphosphate group. In the third segment of the animation, AZT is converted by kinases to AZT-monophosphate (AZT-P), AZT-diphosphate (AZT-PP), and AZT-triphosphate (AZT-PPP), respectively. This step must occur in vivo so that AZT can be successfully incorporated into the replicating strand of DNA. In the final portion of the animation, AZT-PPP is added to the strand. However, AZT lacks the 3'-OH. Instead, it contains N3 at this critical position. Consequently, once it is added, replication comes to a halt. This fact is illustrated in the final segment of the animation where the two base pairs approach the growing strand but are turned away. Therefore, once added to the growing DNA strand, AZT causes DNA chain termination. In doing so, it disrupts the virus' mechanism for replication and survival. Created by: Mike Hanley - Pharmacy StudentMike Hanley Class of 2007 Pharmacy Dr. Parang - Biomedical and Pharmaceutical SciencesDr. Keykavous Parang Assistant Professor Biomedical and Pharmaceutical Sciences College of Pharmacy