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. 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.
Newton
M Gary
MG
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA. newton@secsg.uga.edu
Campana
Charles F
CF
Chi
Guo Chen
GC
Lee
Doowon
D
Liu
Zhi Jie
ZJ
Nair
Vasu
V
Phillips
James
J
Rose
John P
JP
Wang
B C
BC
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
C515521:5'-O-phosphoryl-1'-deoxy-2'-isoadenylyl-3'-5'-cytidine; D019428:HIV Integrase Inhibitors; D007202:Indicators and Reagents; D009841:Oligonucleotides