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Prodrugs of herpes simplex thymidine kinase inhibitors
- Source :
- Antiviral chemistrychemotherapy. 24(2)
- Publication Year :
- 2015
-
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 N2-[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.
- Subjects :
- Guanine
medicine.medical_treatment
Administration, Oral
Biological Availability
Herpesvirus 1, Human
Microbial Sensitivity Tests
medicine.disease_cause
High-performance liquid chromatography
Antiviral Agents
Thymidine Kinase
Mass Spectrometry
Polyethylene Glycols
chemistry.chemical_compound
Mice
Structure-Activity Relationship
medicine
Structure–activity relationship
Animals
Prodrugs
Enzyme Inhibitors
Chromatography, High Pressure Liquid
Dose-Response Relationship, Drug
Molecular Structure
General Medicine
Original Articles
Prodrug
Bioavailability
Herpes simplex virus
chemistry
Biochemistry
Thymidine kinase
Polyvinyls
Adjuvant
Subjects
Details
- ISSN :
- 20402066
- Volume :
- 24
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Antiviral chemistrychemotherapy
- Accession number :
- edsair.doi.dedup.....274728625846314ca7f50355b25cf80a