| Reference | [1]. Biochem Pharmacol. 2017 Jul 15;136:51-61. doi: 10.1016/j.bcp.2017.04.001. Epub 2017 Apr 6.<br />
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.<br />
Balzarini J(1), Menni M(2), Das K(3), van Berckelaer L(4), Ford A(5), Maguire NM(5), Liekens S(4), Boehmer PE(6), Arnold E(3), Götte M(2), Maguire AR(7).<br />
Author information: (1)Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium. Electronic address: [email protected]. (2)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. (3)Center for Advanced Biotechnology and Medicine, and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA. (4)Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium. (5)Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Ireland. (6)Department of Basic Medical Sciences, The University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA. (7)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.<br />
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.<br />
DOI: 10.1016/j.bcp.2017.04.001 PMCID: PMC5557014 PMID: 28390939
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