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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Date
2017-04-06
Authors
Balzarini, Jan
Menni, Michael
Das, Kalyan
van Berckelaer, Lizette
Ford, Alan
Maguire, Nuala M.
Liekens, Sandra
Boehmer, Paul E.
Arnold, Eddy
Götte, Matthias
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Published Version
Abstract
α-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.
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Keywords
Nucleoside/nucleotide analogues , Nucleotide competing RT inhibitor , a-Carboxy nucleoside phosphonates , HIV reverse transcriptase , Herpes DNA polymerase
Citation
Balzarini, 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.2017.04.001