antisense mechanism. It binds to target mRNA, resulting in inhibition of early protein
synthesis within the virus-infected cell. Fomivirsen may even be injected directly into
the eyeball for the treatment of CMV retinitis.
9.3.2 Antivirals Targeting Antiretroviral Mechanisms
The acquired immune deficiency syndrome (AIDS) has become a serious public health
problem around the world, and commands much concern in medical and lay circles
alike. Its causative agent is a human T-cell lymphotropic virus (HIV) that destroys
helper/inducer T cells (discussed in chapter 6) of the immune system and causes mor-
tality by allowing opportunistic infections and malignancies. A compound designed
along traditional lines, 3′-azido-3′-deoxythymidine (9.16, AZT), emerged as one of the
first useful therapeutics. However, since that time many other drugs have been devised.
Drugs designed for the treatment of AIDS function through antiretroviral mecha-
nisms. Antiretroviral agents may be classified into three categories:
- Competitive reverse transcriptase inhibitors
- Non-competitive reverse transcriptase inhibitors
- Protease inhibitors
The first agents to be developed were nucleoside analogs designed to function through
the inhibition of the viral reverse transcriptase enzyme. These agents are also referred
to as nucleoside reverse transcriptase inhibitors(NRTIs). Azidothymidine (AZT) is a
deoxythymidine analog and was the first successful drug in this class. It is an effective
drug, decreasing the rate of clinical disease and prolonging survival. Didanosine (9.17,
ddI) is a synthetic analog of deoxyadenosine; lamivudine (9.18, 3TC) and zalcitabine
(9.19, ddC) are cytosine analogs; stavudine (9.20, d4T) is a thymidine analog; abacavir
(9.21) is a guanosine analog. All of these compounds function as nucleoside reverse
transcriptase inhibitors.
The second class of agents comprises non-competitive inhibitors of reverse tran-
scriptase. These agents are also referred to as non-nucleoside reverse transcriptase
inhibitors (NNRTIs). Unlike NRTIs, NNRTIs do not require phosphorylation to be acti-
vated and do not compete with nucleoside triphosphates. The NNRTIs bind to a site on
the viral reverse transcriptase that is close to but separate from the NRTI receptor site.
This binding ultimately results in blockade of RNA- and DNA-dependent DNA
554 MEDICINAL CHEMISTRY