title: 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.
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.
authors.affiliation: Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium. Electronic address: jan.balzarini@kuleuven.be.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, 6-020 Katz Group Centre, Edmonton AB T6G 2E1, Canada; Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Menni
authors.affiliation: Center for Advanced Biotechnology and Medicine, and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.affiliation: Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Lizette
authors.initials: L
authors.lastname: van Berckelaer
authors.affiliation: Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Ireland.
authors.forename: Alan
authors.initials: A
authors.lastname: Ford
authors.affiliation: Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Ireland.
authors.forename: Nuala M
authors.initials: NM
authors.lastname: Maguire
authors.affiliation: Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
authors.affiliation: Department of Basic Medical Sciences, The University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Boehmer
authors.affiliation: Center for Advanced Biotechnology and Medicine, and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, 6-020 Katz Group Centre, Edmonton AB T6G 2E1, Canada; Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Matthias
authors.initials: M
authors.lastname: Götte
authors.affiliation: Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Ireland; School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Ireland.
authors.forename: Anita R
authors.initials: AR
authors.lastname: Maguire
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism*; D006147:Guanine / Q000737:chemistry / Q000493:pharmacokinetics; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D018259:Herpesvirus 1, Human / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D009705:Nucleosides / Q000737:chemistry / Q000493:pharmacokinetics; D063065:Organophosphonates / Q000737:chemistry / Q000493:pharmacokinetics; D017433:Protein Structure, Secondary
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D009705:Nucleosides; D063065:Organophosphonates; D006147:Guanine; D004259:DNA-Directed DNA Polymerase
keywords: (1R,4S)-(−)-cis-4-acetoxy-2-cyclopenten-1-ol (PubChem CID: 9855498); (1S,4R)-(+)-cis-4-acetoxy-2-cyclopenten-1-ol (PubChem CID: 10154103); (NH(4))(2)SO(4) (PubChem CID: 22921); Bromophenol blue (PubChem CID: 8272); Dithiothreitol (PubChem CID: 446094); EDTA (PubChem CID: 6049); Ethanol (PubChem CID: 702); Formamide (PubChem CID: 713); Glutathione (PubChem CID: 124886); Glycerol (PubChem CID: 753); HIV reverse transcriptase; Herpes DNA polymerase; KCl (PubChem CID: 4873); MgCl(2) (PubChem CID: 5360315); NaCl (PubChem CID: 5234); Nucleoside/nucleotide analogues; Nucleotide competing RT inhibitor; Polyacrylamide (PubChem CID: 6579); Sodium cacodylate (PubChem CID: 2724247); Sodium pyrophosphate (Na(4)P(2)O(7)) (PubChem CID: 24003); Trichloroacetic acid (PubChem CID: 6421); Tris (PubChem CID: 6503); Triton X-100 (PubChem CID: 5590); α-Carboxy nucleoside phosphonates