title: A new nucleoside analogue with potent activity against mutant sr39 herpes simplex virus-1 (HSV-1) thymidine kinase (TK).
abstract: Nucleoside analogues, such as penciclovir, ganciclovir, acyclovir, and their fluoro-substituted derivatives, have wide utility as antivirals. Among these analogues, FHBG ((18)F-Fluorohydroxybutylguanine) is a well-validated PET (positron emission tomography) probe for monitoring reporter gene expression. To evaluate whether or not imposing rigidity into the flexible side chain of FHBG 4 could also impact its interaction, with amino acid residues within the binding site of HSV1-TK (Herpes Simplex Virus-1 Thymidine Kinase), thus influencing its cytotoxic activity. Herein, the synthesis of a new fluorinated nucleoside analogue 6 (conceived via ligand-docking studies) is reported. Agent 6 demonstrates selective activity against HeLa cells stably transfected with mutant HSV1-sr39TK and is also 47-fold more potent than FHBG.
authors: BRIGHT Institute, Molecular Imaging Center, Mallinckrodt Institute of Radiology, Department of Chemistry, Washington University School of Medicine , Box 8225, 510 South Kingshighway Boulevard, St. Louis, Missouri 63110, United States.
authors: G S M
authors: GS
authors: Sundaram
authors: Scott E
authors: SE
authors: Harpstrite
authors: Jeff Lung-Fa
authors: JL
authors: Kao
authors: Silvia D
authors: SD
authors: Collins
authors: Vijay
authors: V
authors: Sharma
mesh_terms: D000212:Acyclovir / Q000737:chemistry* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000737:chemistry* / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D013937:Thymidine Kinase / Q000737:chemistry* / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C113308:9-(4-fluoro-3-hydroxymethylbutyl)guanine; D000998:Antiviral Agents; D009705:Nucleosides; D019275:Radiopharmaceuticals; D014764:Viral Proteins; D006147:Guanine; D013937:Thymidine Kinase; D000212:Acyclovir