Solutions For An Introduction to Medicinal Chemistry Chapter 9 Problem 3Q

The antiviral drug given in the question is zidovudine. It is also called AZT (azidothymidine). The trade name of drug is retrovir. It is an antiretroviral drug that is used for prevention and treatment of HIV/AIDS (Human immunodeficiency virus/ Acquired immunodeficiency syndrome).

The mode of action of AZT is selective inhibition reverse transcriptase (RT) enzyme of HIV. This takes place because AZT is a thymidine analogue. On action of AZT, the HIV DNA is not able to repair the break in the chain.

The mechanism of action of the drug involves activation of the AZT by phosphoryaltion. It is activated to its 5-triphosphate metabolite form. This is ZDV-TP (zidovudine triphosphate).

AZT in presence of dThd (2, 4-dihydroxy thymidine) kinase converts into AZT-MP (azidothymidine monophosphate). Further dTMP (thymidine 5-monophosphate) kinase catalyzes phosphorylation AZT-MP to AZT-DP (azidothymidine diphosphate). Further NDP (nucleoside diphosphate) kinase phosphorylates AZT-DP to AZT-TP.

Figure 1: The figure depicts activation of AZT to AZT-TP/ZDV-TP

This form of the drug competes with thymidne and results in DNA chain termination. This is caused because of inhibition of the activity of HIV RT. It also competes with the dGTP (deoxyguanine triphosphate), natural substrate and incorporates itself into the viral DNA. Given below is the diagrammatic representation of the mechanism:

Figure2: Chain termination caused by to AZT-TP by inhibiting HIV-RT