Guanine a-carboxy nucleoside phosphonate (G-a-CNP) shows a different inhibitory kinetic profile against the DNA polymerases of human immunodeficiency virus (HIV) and herpes viruses

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dc.contributor.authorBalzarini, Jan
dc.contributor.authorMenni, Michael
dc.contributor.authorDas, Kalyan
dc.contributor.authorvan Berckelaer, Lizette
dc.contributor.authorFord, Alan
dc.contributor.authorMaguire, Nuala M.
dc.contributor.authorLiekens, Sandra
dc.contributor.authorBoehmer, Paul E.
dc.contributor.authorArnold, Eddy
dc.contributor.authorGötte, Matthias
dc.contributor.authorMaguire, Anita R.
dc.contributor.funderKU Leuvenen
dc.contributor.funderCanadian Institutes of Health Researchen
dc.contributor.funderNational Institutes of Healthen
dc.date.accessioned2017-06-08T11:18:54Z
dc.date.available2017-06-08T11:18:54Z
dc.date.issued2017-04-06
dc.date.updated2017-06-08T11:09:20Z
dc.description.abstractα-Carboxy nucleoside phosphonates (α-CNPs) are modified nucleotides that represent a novel class of nucleotide-competing reverse transcriptase (RT) inhibitors (NcRTIs). They were designed to act directly against HIV-1 RT without the need for prior activation (phosphorylation). In this respect, they differ from the nucleoside or nucleotide RTIs [N(t)RTIs] that require conversion to their triphosphate forms before being inhibitory to HIV-1 RT. The guanine derivative (G-α-CNP) has now been synthesized and investigated for the first time. The (L)-(+)-enantiomer of G-α-CNP directly and competitively inhibits HIV-1 RT by interacting with the substrate active site of the enzyme. The (D)-(−)-enantiomer proved inactive against HIV-1 RT. In contrast, the (+)- and (−)-enantiomers of G-α-CNP inhibited herpes (i.e. HSV-1, HCMV) DNA polymerases in a non- or uncompetitive manner, strongly indicating interaction of the (L)-(+)- and the (D)-(−)-G-α-CNPs at a location different from the polymerase substrate active site of the herpes enzymes. Such entirely different inhibition profile of viral polymerases is unprecedented for a single antiviral drug molecule. Moreover, within the class of α-CNPs, subtle differences in their sensitivity to mutant HIV-1 RT enzymes were observed depending on the nature of the nucleobase in the α-CNP molecules. The unique properties of the α-CNPs make this class of compounds, including G-α-CNP, direct acting inhibitors of multiple viral DNA polymerases.en
dc.description.sponsorshipKU Leuven (GOA 15/19 TBA); National Institutes of Health (NIH grants R37 AI027690, R03 AI119430)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationBalzarini, J., Menni, M., Das, K., van Berckelaer, L., Ford, A., Maguire, N. M., Liekens, S., Boehmer, P. E., Arnold, E., Götte, M. and Maguire, A. R. (2017) 'Guanine α-carboxy nucleoside phosphonate (G-α-CNP) shows a different inhibitory kinetic profile against the DNA polymerases of human immunodeficiency virus (HIV) and herpes viruses', Biochemical Pharmacology, 136, pp. 51-61. doi:10.1016/j.bcp.2017.04.001en
dc.identifier.doi10.1016/j.bcp.2017.04.001
dc.identifier.endpage61en
dc.identifier.issn0006-2952
dc.identifier.journaltitleBiochemical Pharmacologyen
dc.identifier.startpage51en
dc.identifier.urihttps://hdl.handle.net/10468/4063
dc.identifier.volume136en
dc.language.isoenen
dc.publisherElsevieren
dc.rights© 2017 Elsevier Inc. This manuscript version is made available under the CC-BY-NC-ND 4.0 licenseen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectNucleoside/nucleotide analoguesen
dc.subjectNucleotide competing RT inhibitoren
dc.subjecta-Carboxy nucleoside phosphonatesen
dc.subjectHIV reverse transcriptaseen
dc.subjectHerpes DNA polymeraseen
dc.titleGuanine a-carboxy nucleoside phosphonate (G-a-CNP) shows a different inhibitory kinetic profile against the DNA polymerases of human immunodeficiency virus (HIV) and herpes virusesen
dc.typeArticle (peer-reviewed)en
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