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

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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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