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NH
2
O
NH
2
N
N
R
NH
N
O
N
N
HO
OH
N
O
P
O
O
N
R
O
O
R
S
N
3
3. R = F
5
1. R = OH
O
2. R =
O
4. R = H
O
i
Pr
O
OH
HN
F
3
C
N
N
N
N
Cl
O
HO
HO
N
N
N
N
NH
2
O
H
O
8
7
6
Figure 10.1
Structures of FDA approved N(t)RTI and NNRTIs.
respectively], and non-nucleoside inhibitors (NNRTIs). Examples of each class
are shown in Figure 10.1.
Tenofovir disoproxil fumarate (TDF, 2), a prodrug of tenofovir (TFV, 1), is
the only nucleotide analog approved for HIV treatment. Examples of NRTIs
include emtricitabine (FTC, 3), lamivudine (3TC, 4), zidovudine (AZT, 5),
didanosine (ddI, 6), and abacavir (ABC, 7), whilst efavirenz (EFV, 8)isan
example of a NNRTI. Collectively the N(t)RTIs inhibit RT by competing with
the natural deoxynucleotide triphosphate substrates at the active site, whereas
the NNRTIs bind to an allosteric site on RT and block conformational
changes required for ecient polymerization to occur. In 1995-1996, the first
HIV protease inhibitors were approved and thus began the era of combination
treatment now known as highly active antiretroviral therapy (HAART).
The early HAART regimens required the administration of drugs according to
complex dosing schedules and inevitably led to poor patient compliance,
which in turn resulted in the emergence of resistance.
4
Therefore, major efforts
across the pharmaceutical industry have been invested into the development of
simplified HIV regimens, culminating in the approval of Atripla
t
, the first
single-pill, once-daily (qd) complete regimen for HIV treatment. Atripla
t
combines three qd drugs, 2, 3, and 8, all of which target RT, emphasizing
the critical importance of RT inhibitors in HIV therapy. Indeed the combi-
nation of two N(t)RTIs has become the backbone of choice for many HAART
regimens.
5
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