Nucleic Acids in Chemistry and Biology

Large randomized and cohort studies on asymptomatic patients have demonstrated that non-nucleoside
reverse-transcriptase inhibitors are at least as effective as protease inhibitors as part of initial triple-drug
therapy. The effectiveness of specific highly active antiretroviral therapy (HAART) combinations has pro-
vided support for the use of triple therapy with zidovudine, lamivudine (Combivir) and efavirenz (ZDV/
3TC/EFV).^131
Various new NRTIs and NNRTIs have been developed that possess improved metabolic characteristics
(i.e.phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the
NRTIs) or increased activity (‘second’ or ‘third’ generation NNRTIs (i.e.TMC-125, DPC-083)) against those
HIV strains which are resistant to the ‘first’ generation NNRTIs.

3.7.2.1.3 Protease Inhibitors. The HIV protease is a vital enzyme in the HIV life cycle that cleaves

the transcribed gag-polprotein into three HIV polypeptides: the RT, integrase and gagpolypeptides. Six HIV
protease inhibitors have been approved of which saquinavir and ritonavir are two widely used analogues.
The use of combination therapies against HIV that employ two nucleoside-based RT inhibitors together with
a PI agent are now proving to be highly effective, as for example, the combination of zidovudine (AZT)
and stavudine (d4T) along with a PI such as indinavir. It appears that triple-drug regimens containing two
NRTIs with a PI, a NNRTI or a third NRTI may provide comparable activity.^132

3.7.2.1.4 Host-Cell Receptor Based Therapeutic Agents. A virus initiates infection by attach-

ing to a specific receptor on the surface of a susceptible host cell. Agents that inhibit such virus–receptor
interactions in the case of HIV and its CD4 receptor on T lymphocytes are in clinical trial for AIDS.
However, approaches of this type do not involve the use of nucleoside or nucleotide analogues and will not
be discussed further.
Finally, we have to recognise that host-cell toxicity is a major problem. Many nucleoside drugs are
directed at enzymes (such as polymerases) that have counterparts in host cells and it is often inevitable that
they may interfere with a fundamental biochemical pathway in a normal cell. Because such toxicity is fre-
quently unacceptable for non-life-threatening disease states, extensive testing is inevitable, time consuming,
and inordinately expensive. In contrast, ‘fast-tracking’ of new candidate drugs is available for life-threatening

132 Chapter 3

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Figure 3.91 Non-nucleoside HIV reverse transcriptase inhibitors: (a) TIBO class; (b) HEPT class; (c) Nevirapine;
(d) Delavirdine; (e) Efavirenz

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