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Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates
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Accepted Version
Date
2016-01-19
Authors
Mullins, Nicholas D.
Maguire, Nuala M.
Ford, Alan
Das, Kalyan
Arnold, Eddy
Balzarini, Jan
Maguire, Anita R.
Journal Title
Journal ISSN
Volume Title
Publisher
Royal Society of Chemistry
Published Version
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.
Description
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
Copyright
© 2016, Royal Society of Chemistry.