The Discovery of Zidovudine

 Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication
typically used to treat HIV infection in adults and children +4 weeks old and to prevent mother-
to-child transmission of HIV1
. ZDV was first described by Jerome P. Horowitz at the Barbara Ann
Karmanos Cancer Institute as a part of an NIH funded anticancer program2
. Unfortunately, the
compound showed no anticancer activity when tested on leukemic mice3
. ZDV was then
shelved. It was not until May 20, 1983, when researchers at the Institut Pasteur identified the
retrovirus now known as HIV, that ZDV was revisited as a possible therapeutic4
. This led
research efforts to focus on a key enzyme, reverse transcriptase, as a target. A paper was
published in October 1985 that demonstrated ZDV; (1) produced nearly no toxicity even at high
doses to mice and dogs, (2) essentially completely inhibited viral replication without effecting T-
cell immune reactivity, and (3) could be absorbed through oral administration5
. On March 20,
1987, ZDV was FDA approved for use against HIV and AIDS. Only a short period of time had
passed between demonstrated efficacy and FDA approval.
The mechanism of action is rather elegant and simple. ZDV belongs to the nucleoside
analog reverse-transcriptase inhibitor (NARTI) class of reverse-transcriptase inhibitors and
works because it is an analogue of the endogenous thymidine nucleoside. ZDV, in its inactive
form, enters the cell and must be successively phosphorylated by cellular kinase enzymes,
eventually yielding Zidovudine-triphosphate (ZDV-TP). ZDV-TP can then be incorporated into
the growing DNA strand by the virus’ reverse-transcriptase enzyme. It has been shown that ͞…
a relationship between the observed inhibitory effects of both AZT and nevirapine and the
length of target template makes it unlikely that these drugs have any direct effect on [reverse
transcriptase] through mechanisms other than direct inhibition of viral DNA chain elongation6
.͟
This chain termination occurs because the deoxynucleotide that follows ZDV cannot form the 5’
3’ phosphodiester bond thus halting DNA elongation. While the safety of inhibiting DNA
elongation is certainly a cause for concern, ZDV has been shown to inhibit HIV replication
between 50-500 nM whereas inhibition of human fibroblasts and lymphocytes occurs at
concentrations > 1 mM7
. Furthermore, it has been theorized that cellular repair enzymes
present in human cells are able to remove ZDV from the growing DNA strand. HIV has no such
mechanism, which helps explain the noted low toxicity for human cells and high toxicity for the
virus8
. However, there are some adverse effects including flu-like symptoms, kidney and liver
problems, and lipodystrophy9
.
Regarding this assignment, it was somewhat surprising to discover that the newer
generation of HIV medication, Nevirapine, is less effective than Zidovudine. This is because
Nevirapine binds at the polymerase active site which can easily mutate to prevent binding. This
is the case with HIV-2, against which Nevirapine is ineffective10
. Resistance to ZDV can occur,
though can be overcome when used in conjunction with foscarnet11
. Future development for
ZDV may be limited. ZDV has been used for over three decades and long-term use is associated with resistance, though the mechanism of directly interrupting DNA elongation may continue to
be utilized within HIV research.