Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates

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Date
2016-01-19
Authors
Mullins, Nicholas D.
Maguire, Nuala M.
Ford, Alan
Das, Kalyan
Arnold, Eddy
Balzarini, Jan
Maguire, Anita R.
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Royal Society of Chemistry
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Abstract
As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed. The malonate derivative 2 was less active by two orders of magnitude than the original α-CNPs, while displaying the same pattern of kinetic behavior; interestingly the activity resides in the “L”-enantiomer of 2, as seen with the earlier series of α-CNPs. A crystal structure with an RT/DNA complex at 2.95 Å resolution revealed the binding of the “L”-enantiomer of 2, at the polymerase active site with a weaker metal ion chelation environment compared to 1a (T-α-CNP) which may explain the lower inhibitory activity of 2.
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Keywords
HIV-1 reverse transcriptase , Inhibitory activity , Kinetic behavior , Metal-ion chelation , Orders of magnitude , Polymerase active site , Reverse transcriptases
Citation
MULLINS, N. D., MAGUIRE, N. M., FORD, A., DAS, K., ARNOLD, E., BALZARINI, J. and MAGUIRE, A. R. (2016) ‘Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates’, Organic and Biomolecular Chemistry, 14, 2454-2465. doi:10.1039/C5OB02507A
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© 2016, Royal Society of Chemistry.