Balzarini, Jan; Menni, Michael; Das, Kalyan; van Berckelaer, Lizette; Ford, Alan; Maguire, Nuala M.; Liekens, Sandra; Boehmer, Paul E.; Arnold, Eddy; Götte, Matthias; Maguire, Anita R.

2017

Unknown

Biochemical Pharmacology

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

Validated

Altmetric: 2 ()

Nucleoside/nucleotide analogues Nucleotide competing RT inhibitor a-Carboxy nucleoside phosphonates HIV reverse transcriptase Herpes DNA polymerase

136

51

61

a-Carboxy nucleoside phosphonates (a-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-a-CNP) has now been synthesized and investigated for the first time. The (L)-(+)-enantiomer of G-a-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-a-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-a-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 a-CNPs, subtle differences in their sensitivity to mutant HIV-1 RT enzymes were observed depending on the nature of the nucleobase in the a-CNP molecules. The unique properties of the a-CNPs make this class of compounds, including G-a-CNP, direct acting inhibitors of multiple viral DNA polymerases.

0006-2952

10.1016/j.bcp.2017.04.001