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.

Autor: Balzarini J; Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium. Electronic address: jan.balzarini@kuleuven.be., Menni M; 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., Das K; Center for Advanced Biotechnology and Medicine, and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA., van Berckelaer L; Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium., Ford A; Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Ireland., Maguire NM; Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Ireland., Liekens S; Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium., Boehmer PE; Department of Basic Medical Sciences, The University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA., Arnold E; Center for Advanced Biotechnology and Medicine, and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA., Götte M; 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., Maguire AR; 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.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2017 Jul 15; Vol. 136, pp. 51-61. Date of Electronic Publication: 2017 Apr 06.
DOI: 10.1016/j.bcp.2017.04.001
Abstrakt: 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.
(Copyright © 2017 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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