title: Prodrugs of herpes simplex thymidine kinase inhibitors.
abstract: BACKGROUND
  Because guanine-based herpes simplex virus thymidine kinase inhibitors are not orally available, we synthesized various 6-deoxy prodrugs of these compounds and evaluated them with regard to solubility in water, oral bioavailability, and efficacy to prevent herpes simplex virus-1 reactivation from latency in a mouse model.
  
  
  METHODS
  Organic synthesis was used to prepare compounds, High Performance Liquid Chromatography (HPLC) to analyze hydrolytic conversion, Mass Spectrometry (MS) to measure oral bioavailability, and mouse latent infection and induced reactivation to evaluate the efficacy of a specific prodrug.
  
  
  RESULTS
  Aqueous solubilities of prodrugs were improved, oxidation of prodrugs by animal cytosols occurred in vitro, and oral absorption of the optimal prodrug sacrovir™ (6-deoxy-mCF3PG) in the presence of the aqueous adjuvant Soluplus® and conversion to active compound N(2)-[3-(trifluoromethyl)pheny])guanine (mCF3PG) were accomplished in mice. Treatment of herpes simplex virus-1 latent mice with sacrovir™ in 1% Soluplus in drinking water significantly suppressed herpes simplex virus-1 reactivation and viral genomic replication.
  
  
  CONCLUSIONS
  Ad libitum oral delivery of sacrovir™ was effective in suppressing herpes simplex virus-1 reactivation in ocularly infected latent mice as measured by the numbers of mice shedding infectious virus at the ocular surface, numbers of trigeminal ganglia positive for infectious virus, number of corneas that had detectable infectious virus, and herpes simplex virus-1 genome copy numbers in trigeminal ganglia following reactivation. These results demonstrate the statistically significant effect of the prodrug on suppressing herpes simplex virus-1 reactivation in vivo.
authors.affiliation: GLSynthesis Inc. One Innovation Drive, Worcester, USA.
authors.forename: Milka
authors.initials: M
authors.lastname: Yanachkova
authors.affiliation: GLSynthesis Inc. One Innovation Drive, Worcester, USA Yancheng Tianhai Pharma Inc., Yancheng, China.
authors.forename: Wei-Chu
authors.initials: WC
authors.lastname: Xu
authors.affiliation: GLSynthesis Inc. One Innovation Drive, Worcester, USA.
authors.forename: Sofya
authors.initials: S
authors.lastname: Dvoskin
authors.affiliation: GLSynthesis Inc. One Innovation Drive, Worcester, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Dix
authors.affiliation: GLSynthesis Inc. One Innovation Drive, Worcester, USA.
authors.forename: Ivan B
authors.initials: IB
authors.lastname: Yanachkov
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionalle delle Ricerche, Pavia, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Focher
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionalle delle Ricerche, Pavia, Italy.
authors.forename: Lida
authors.initials: L
authors.lastname: Savi
authors.affiliation: Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA Department of Ophthalmology, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA.
authors.forename: M Dulfary
authors.initials: MD
authors.lastname: Sanchez
authors.affiliation: Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA Department of Ophthalmology, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Foster
authors.affiliation: GLSynthesis Inc. One Innovation Drive, Worcester, USA george.wright@glsynthesis.com.
authors.forename: George E
authors.initials: GE
authors.lastname: Wright
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology*; D013058:Mass Spectrometry; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry; D011145:Polyvinyls / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C000609255:N2-(3-(trifluoromethyl)pheny)-6-deoxyguanine; D011145:Polyvinyls; D011355:Prodrugs; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D011092:Polyethylene Glycols; D006147:Guanine; D013937:Thymidine Kinase
keywords: Compounds; Herpes simplex virus; latency; prodrugs; thymidine kinase