Table 1. . Inhibitory activity of the L-enantiomeric alpha-carboxynucleoside phosphonates against HIV-1 reverse transcriptase in the presence of different homopolymeric template/primers.
| Compound† | IC50‡,§ HIV-1 RT (μM) | |||
|---|---|---|---|---|
| Poly rA.dT ([3H]dTTP) | Poly rI.dC ([3H]dCTP) | Poly rU.dA ([3H]dATP) | Poly rC.dG ([3H]dGTP) | |
| T-α-CNP | 0.41# | >500 | 155 | >100 |
| U-α-CNP | 3.0# | >500 | 208 | – |
| C-α-CNP | 164 | 4.3# | 45 | – |
| A-α-CNP | >500 | >500 | 0.19# | – |
| G-α-CNP | 396 | – | – | 0.43# |
| AZT-TP | 0.11 | – | – | – |
| ddCTP | – | 14 | – | – |
| ddATP | – | – | 1.5 | – |
| ddGTP | – | – | – | 0.41 |
Inhibition of RTs by T-, U-, C-, A- and G-α-CNP analogs was evaluated using the respective homopolymeric template/primers poly rA.dT (for T- and U-α-CNP), poly rI.dC (for C-α-CNP), poly rU.dA (for A-α-CNP) and poly rC.dG (for G-α-CNP) and ∼1.25–2.5 μM of their appropriate corresponding dNTP substrates [CH3-3H]dTTP (for T- and U-α-CNP), [5-3H]dCTP (for C-α-CNP), [2,8-3H]dATP (for A-α-CNP) and [2,8-3H]dGTP (for G-α-CNP).
†Each α-CNP represents a pair of diastereomers at the alpha-carboxy stereocenter.
‡50% inhibitory concentration or compound concentration required to inhibit DNA polymerase activity by 50%.
#Pronounced activities of the alpha-CNPs.
α-CNP: Alpha-carboxynucleoside phosphonate; ATP: Adenine triphosphate; AZT-TP: Zidovudine triphosphate; CTP: Cytosine triphosphate; dNTP: 2’-Deoxyucleotide-5’-triphosphate; GTP: Guanine triphosphate; RT: Reverse transcriptase.