Alpha-carboxy nucleoside phosphonates as universal nucleoside triphosphate mimics

Jan Balzarini, Kalyan Das, Jean A. Bernatchez, Sergio E. Martinez, Marianne Ngure, Sarah Keane, Alan Ford, Nuala Maguire, Niki Mullins, Jubi John, Youngju Kim, Wim Dehaen, Johan Vande Voorde, Sandra Liekens, Lieve Naesens, Matthias Götte, Anita R. Maguire, Eddy Arnold

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Polymerases have a structurally highly conserved negatively charged amino acid motif that is strictly required for Mg2+ cation-dependent catalytic incorporation of (d)NTP nucleotides into nucleic acids. Based on these characteristics, a nucleoside monophosphonate scaffold, α-carboxy nucleoside phosphonate (α-CNP), was designed that is recognized by a variety of polymerases. Kinetic, biochemical, and crystallographic studies with HIV-1 reverse transcriptase revealed that α-CNPs mimic the dNTP binding through a carboxylate oxygen, two phosphonate oxygens, and base-pairing with the template. In particular, the carboxyl oxygen of the α-CNP acts as the potential equivalent of the α-phosphate oxygen of dNTPs and two oxygens of the phosphonate group of the α-CNP chelate Mg2+, mimicking the chelation by the β- and γ-phosphate oxygens of dNTPs. α-CNPs (i ) do not require metabolic activation (phosphorylation), (ii ) bind directly to the substrate-binding site, (iii ) chelate one of the two active site Mg2+ ions, and (iv) reversibly inhibit the polymerase catalytic activity without being incorporated into nucleic acids. In addition, α-CNPs were also found to selectively interact with regulatory (i.e., allosteric) Mg2+-dNTP-binding sites of nucleos(t)ide-metabolizing enzymes susceptible to metabolic regulation. α-CNPs represent an entirely novel and broad technological platform for the development of specific substrate active- or regulatory-site inhibitors with therapeutic potential.

Original languageEnglish (US)
Pages (from-to)3475-3480
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
StatePublished - Mar 17 2015

All Science Journal Classification (ASJC) codes

  • General


  • (Deoxy)nucleoside triphosphate mimic
  • Allosteric inhibition
  • Alpha-carboxy nucleoside phosphonate
  • HIV reverse transcriptase
  • Herpes virus DNA polymerase


Dive into the research topics of 'Alpha-carboxy nucleoside phosphonates as universal nucleoside triphosphate mimics'. Together they form a unique fingerprint.

Cite this