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

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)51-61
Number of pages11
JournalBiochemical Pharmacology
Volume136
DOIs
StatePublished - Jul 15 2017

Fingerprint

Organophosphonates
Guanine
DNA-Directed DNA Polymerase
Viruses
Nucleosides
HIV
Kinetics
Enantiomers
Nucleotides
Catalytic Domain
Enzymes
Phosphorylation
Molecules
Reverse Transcriptase Inhibitors
Viral DNA
Human Herpesvirus 1
Substrates
Antiviral Agents
Chemical activation
Human immunodeficiency virus 1 reverse transcriptase

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

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. / 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.

In: Biochemical Pharmacology, Vol. 136, 15.07.2017, p. 51-61.

Research output: Contribution to journalArticle

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. / 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. In: Biochemical Pharmacology. 2017 ; Vol. 136. pp. 51-61.
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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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AU - Balzarini, Jan

AU - Menni, Michael

AU - Das, Kalyan

AU - van Berckelaer, Lizette

AU - Ford, Alan

AU - Maguire, Nuala M.

AU - Liekens, Sandra

AU - Boehmer, Paul E

AU - Arnold, Eddy

AU - Götte, Matthias

AU - Maguire, Anita R.

PY - 2017/7/15

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