Understanding how the herpes thymidine kinase orchestrates optimal sugar and nucleobase conformations to accommodate its substrate at the active site: a chemical approach.
The herpes virus thymidine kinase (HSV-tk) is a critical enzyme for the activation of anti-HSV nucleosides. However, a successful therapeutic outcome depends not only on the activity of this enzyme but also on the ability of the compound(s) to interact effectively with cellular kinases and with the target viral or cellular DNA polymerases. Herein, we describe the synthesis and study of two nucleoside analogues built on a conformationally locked bicyclo[3.1.0]hexane template designed to investigate the conformational preferences of HSV-tk for the 2'-deoxyribose ring. Intimately associated with the conformation of the 2'-deoxyribose ring is the value of the C-N torsion angle chi, which positions the nucleobase into two different domains (syn or anti). The often-conflicting sugar and nucleobase conformational parameters were studied using North and South methanocarbadeoxythymidine analogues (6 and 7), which forced HSV-tk to make a clear choice in the conformation of the substrate. The results provide new insights into the mechanism of action of this enzyme, which cannot be gleaned from a static X-ray crystal structure.
Marquez
Victor E
VE
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA. marquezv@dc37a.nci.nih.gov
Choi
Yongseok
Y
Comin
Maria Julieta
MJ
Russ
Pamela
P
George
Clifford
C
Huleihel
Mahmoud
M
Ben-Kasus
Tsipi
T
Agbaria
Riad
R
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D002241:Carbohydrates / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003855:Deoxyribose / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006561:Herpes Simplex / Q000201:enzymology*; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry*; D013379:Substrate Specificity; D013936:Thymidine / Q000737:chemistry; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
D000998:Antiviral Agents; D001643:Bridged Bicyclo Compounds; D002241:Carbohydrates; D004791:Enzyme Inhibitors; D009705:Nucleosides; C046059:bicyclo(3.1.0)hexane; D003855:Deoxyribose; D013937:Thymidine Kinase; D013936:Thymidine