A non-natural dinucleotide containing an isomeric L-related deoxynucleoside : Dinucleotide inhibitors of anti-HIV integrase activity

The first X-ray crystal structure of a non-natural dinucleotide, 5'-O-phosphoryl-1'-deoxy-2'-isoadenylyl-(3' --> 5')-cytidine 6.5-hydrate (pIsodApC), C19H26N8O13P2 x 6.5H2O, belonging to a family of dinucleotides that contain an isomeric nucleoside component, is described...

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Bibliographic Details
Published in:Acta crystallographica. Section C, Crystal structure communications Crystal structure communications, 2005-08, Vol.61 (Pt 8), p.o518-o520
Main Authors: NEWTON, M. Gary, CAMPANA, Charles F, CHI, Guo-Chen, LEE, Doowon, LIU, Zhi-Jie, NAIR, Vasu, PHILLIPS, James, ROSE, John P, WANG, B.-C
Format: Article
Language:English
Subjects:
Condensed matter: structure, mechanical and thermal properties
Crystalline state (including molecular motions in solids)
Crystallography, X-Ray
Exact sciences and technology
HIV Integrase Inhibitors - chemical synthesis
HIV Integrase Inhibitors - chemistry
Hydrogen Bonding
Indicators and Reagents
Magnetic Resonance Spectroscopy
Mass Spectrometry
Models, Molecular
Molecular Conformation
Oligonucleotides - chemical synthesis
Oligonucleotides - chemistry
Physics
Spectrophotometry, Ultraviolet
Structure of solids and liquids
crystallography
Structure of specific crystalline solids
Theory of crystal structure, crystal symmetry
calculations and modeling
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Summary:The first X-ray crystal structure of a non-natural dinucleotide, 5'-O-phosphoryl-1'-deoxy-2'-isoadenylyl-(3' --> 5')-cytidine 6.5-hydrate (pIsodApC), C19H26N8O13P2 x 6.5H2O, belonging to a family of dinucleotides that contain an isomeric nucleoside component, is described. A complex system of hydrogen bonds between water molecules and various sites on the dinucleotide was found. All H atoms were located from electron-density difference maps, which allowed identification of protonation sites. Compounds of this family have been found to bind at the active site of HIV integrase and to be inhibitors of this key viral enzyme. These dinucleotides are completely resistant to cleavage by exonucleases; an abnormal dihedral angle twist in an internucleotide phosphate bond revealed in the X-ray crystal structure may be contributing to this unusual stability towards nucleases.
ISSN:0108-2701
1600-5759
DOI:10.1107/S0108270105019037