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

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


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