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through reduction of host mitochondrial DNA synthesis.
22
This raised the
question as to whether selectivity toward HIV RT can be improved. Most
nucleoside analogs have
D
-configurations like the natural substrates, but HIV
RT can accommodate
L
-configured analogs as exemplified by 3 and 4. Typically
the
L
-analogs demonstrate good selectivity for HIV RT compared to
mitochondrial polymerases, which suggested that the
L
-isomer 21 shown in
Table 10.3 may be a promising solution to the selectivity issue.
23
A second
potential solution also shown in Table 10.3 is fluoro analog 22, rationally
designed based on comparing the active site models of 15-DP bound in HIV RT
and DNA polymerase g (Figure 10.4).
24,25
Based on differences in the active site close to the 2
0
-position of the 15-DP
inhibitor, introduction of a 2
0
-fluorine atom was proposed to reduce binding to
DNA polymerase g yet retain good binding for HIV RT. Literature reports
concerning 2
0
-b-F substitution onto saturated dd ribose nucleosides also
described reduced inhibition of mitochondrial DNA polymerase g and pro-
vided the final impetus to pursue this rationally designed target despite a
challenging synthesis.
26,27
Both analogs 21 and 22 (GS-9148) were devoid of
mitochondrial cell toxicity up to concentrations of 300 mM (Table 10.3).
28
The
2
0
-F analog diphosphate metabolite 22-DP demonstrated weak inhibition of
the host mitochondrial polymerases and was only 3- and 5-fold less potent than
15-DP and 1-DP, respectively, toward HIV RT. Consistent with this reduced
potency toward RT, the antiviral activity of 22 was also marginally weaker
than 15 and 1. The unnatural
L
-isomer 21 was poorly active toward the M184V
and 6TAMs RT mutations, whilst the 2
0
-F analog 22 was essentially identical
to 15. Overall, analog 22 demonstrated a very promising in vitro profile,
HIV RT
HIV RT
DNA Polymerase
DNA Polymerase γ
15-DP
15-DP
15-DP
15-DP
Gln151
Gln151
Tyr951
Tyr951
Figure 10.4
Binding models of 15-DP in the active site of HIV RT and mitochondrial
polymerase g.
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