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

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dc.check.date2017-01-19
dc.check.infoAccess to this article is restricted until 12 months after publication by request of the publisher.en
dc.contributor.authorMullins, Nicholas D.
dc.contributor.authorMaguire, Nuala M.
dc.contributor.authorFord, Alan
dc.contributor.authorDas, Kalyan
dc.contributor.authorArnold, Eddy
dc.contributor.authorBalzarini, Jan
dc.contributor.authorMaguire, Anita R.
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderNational Institutes of Healthen
dc.contributor.funderKU Leuvenen
dc.date.accessioned2016-11-08T10:09:14Z
dc.date.available2016-11-08T10:09:14Z
dc.date.issued2016-01-19
dc.description.abstractAs 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.sponsorshipScience 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.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMULLINS, 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/C5OB02507Aen
dc.identifier.doi10.1039/C5OB02507A
dc.identifier.endpage2465en
dc.identifier.issn1477-0520
dc.identifier.journaltitleOrganic and Biomolecular Chemistryen
dc.identifier.startpage2454en
dc.identifier.urihttps://hdl.handle.net/10468/3254
dc.identifier.volume14en
dc.language.isoenen
dc.publisherRoyal Society of Chemistryen
dc.rights© 2016, Royal Society of Chemistry.en
dc.subjectHIV-1 reverse transcriptaseen
dc.subjectInhibitory activityen
dc.subjectKinetic behavioren
dc.subjectMetal-ion chelationen
dc.subjectOrders of magnitudeen
dc.subjectPolymerase active siteen
dc.subjectReverse transcriptasesen
dc.titleExploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonatesen
dc.typeArticle (peer-reviewed)en
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