Nucleoside diphosphate kinase and the activation of antiviral phosphonate analogs of nucleotides: binding mode and phosphorylation of tenofovir derivatives.

Abstract

Tenofovir is an acyclic phosphonate analog of deoxyadenylate used in AIDS and hepatitis B therapy. We find that tenofovir diphosphate, its active form, can be produced by human nucleoside diphosphate kinase (NDPK), but with low efficiency, and that creatine kinase is significantly more active. The 1.65 A x-ray structure of NDPK in complex with tenofovir mono- and diphosphate shows that the analogs bind at the same site as natural nucleotides, but in a different conformation, and make only a subset of the Van der Waals and polar interactions made by natural substrates, consistent with their comparatively low affinity for the enzyme.

• Authors: Kerstin Koch, Yuxing Chen, Joy Y Feng, Katyna Borroto-Esoda, Dominique Deville-Bonne, Sarah Gallois-Montbrun, Joël Janin, Solange Moréra
• Journal: Nucleosides, nucleotides & nucleic acids (Nucleosides Nucleotides Nucleic Acids) Vol. 28 Issue 8 Pg. 776-92 (Aug 2009) ISSN: 1532-2335 [Electronic] United States
• PMID: 20183617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Nucleotides
• Organophosphonates
• Recombinant Proteins
• Reverse Transcriptase Inhibitors
• Tenofovir
• Nucleoside-Diphosphate Kinase
• Adenine

Topics

• Adenine (analogs & derivatives, chemistry, pharmacology)
• Antiviral Agents (pharmacology)
• Binding Sites
• Crystallography, X-Ray
• Dictyostelium (enzymology)
• Escherichia coli (genetics)
• Humans
• Models, Molecular
• Nucleoside-Diphosphate Kinase (chemistry, metabolism)
• Nucleotides (chemistry)
• Organophosphonates (chemistry, pharmacology)
• Phosphorylation (drug effects)
• Recombinant Proteins (chemistry, genetics, metabolism)
• Reverse Transcriptase Inhibitors (chemistry, pharmacology)
• Substrate Specificity
• Tenofovir