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R. L. Mackman et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6785–6789
Figure 2. (a) Compound 2 and (b) compound 18 bound in WT HIV RT. M184 interacts more closely to the 40-CH2 in (b) due to the different
puckering of the isomeric ribose ring compared to compound 2.
indicates that the nucleobase has an important role in
reducing the propensity for excision. Comparing the
TAMs profiles for four adenine analogs, acyclic phos-
phonate tenofovir 1 (8.8-fold resistance), d4 analog 2
(2.9-fold resistance), dd analog 4 (3.4-fold resistance),
and iso-analog 18 (3.2-fold resistance), indicates how
differences in the ribose portion of the molecule affect
the antiviral resistance due to TAMs. Further studies
that examined the in vitro removal of the four adenine
analogs from the 30-terminated DNA primer by RT
indicated that the cyclic analogs displayed reduced
efficiency of excision compared to tenofovir (data
not shown). These data corroborate the differences
in the TAMs susceptibility observed in the antiviral
assays. Taken together, cyclic ribose phosphonates
containing adenine base exhibit the most favorable
TAMs resistance profile among all tested nucleotide
analogs.
d4AP 2 has a superior resistance profile to both iso-
ddAP 18 and tenofovir 1, the only FDA-approved
NtRTI.
References and notes
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