title: A non-natural dinucleotide containing an isomeric L-related deoxynucleoside: dinucleotide inhibitors of anti-HIV integrase activity.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA. newton@secsg.uga.edu
authors.forename: M Gary
authors.initials: MG
authors.lastname: Newton
authors.forename: Charles F
authors.initials: CF
authors.lastname: Campana
authors.forename: Guo Chen
authors.initials: GC
authors.lastname: Chi
authors.forename: Doowon
authors.initials: D
authors.lastname: Lee
authors.forename: Zhi Jie
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Vasu
authors.initials: V
authors.lastname: Nair
authors.forename: James
authors.initials: J
authors.lastname: Phillips
authors.forename: John P
authors.initials: JP
authors.lastname: Rose
authors.forename: B C
authors.initials: BC
authors.lastname: Wang
mesh_terms: D018360:Crystallography, X-Ray; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D008968:Molecular Conformation; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet
chemical_list: C515521:5'-O-phosphoryl-1'-deoxy-2'-isoadenylyl-3'-5'-cytidine; D019428:HIV Integrase Inhibitors; D007202:Indicators and Reagents; D009841:Oligonucleotides