dc.contributor.author |
Mullins, Nicholas D. |
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dc.contributor.author |
Maguire, Nuala M. |
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dc.contributor.author |
Ford, Alan |
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dc.contributor.author |
Das, Kalyan |
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dc.contributor.author |
Arnold, Eddy |
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dc.contributor.author |
Balzarini, Jan |
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dc.contributor.author |
Maguire, Anita R. |
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dc.date.accessioned |
2016-11-08T10:09:14Z |
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dc.date.available |
2016-11-08T10:09:14Z |
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dc.date.issued |
2016-01-19 |
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dc.identifier.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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dc.identifier.volume |
14 |
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dc.identifier.startpage |
2454 |
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dc.identifier.endpage |
2465 |
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dc.identifier.issn |
1477-0520 |
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dc.identifier.uri |
http://hdl.handle.net/10468/3254 |
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dc.identifier.doi |
10.1039/C5OB02507A |
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dc.description.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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dc.description.sponsorship |
Science Foundation Ireland (05/PICA/B802 and SFI 14/TIDA/2402); National Institutes of Health (Grant R37 MERIT Award AI27690); KU Leuven (GOA 15/19 TBA) |
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dc.format.mimetype |
application/pdf |
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dc.language.iso |
en |
en |
dc.publisher |
Royal Society of Chemistry |
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dc.rights |
© 2016, Royal Society of Chemistry. |
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dc.subject |
HIV-1 reverse transcriptase |
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dc.subject |
Inhibitory activity |
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dc.subject |
Kinetic behavior |
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dc.subject |
Metal-ion chelation |
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dc.subject |
Orders of magnitude |
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dc.subject |
Polymerase active site |
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dc.subject |
Reverse transcriptases |
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dc.title |
Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates |
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dc.type |
Article (peer-reviewed) |
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dc.internal.authorcontactother |
Anita Maguire, Chemistry, University College Cork, Cork, Ireland. +353-21-490-3000 Email: a.maguire@ucc.ie |
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dc.internal.availability |
Full text available |
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dc.check.info |
Access to this article is restricted until 12 months after publication by request of the publisher. |
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dc.check.date |
2017-01-19 |
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dc.description.version |
Accepted Version |
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dc.contributor.funder |
Science Foundation Ireland
|
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dc.contributor.funder |
National Institutes of Health
|
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dc.contributor.funder |
KU Leuven
|
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dc.description.status |
Peer reviewed |
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dc.identifier.journaltitle |
Organic and Biomolecular Chemistry |
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dc.internal.IRISemailaddress |
a.maguire@ucc.ie |
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dc.internal.IRISemailaddress |
a.maguire@ucc.ie |
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