{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T02:10:22Z","timestamp":1725415822678},"reference-count":18,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2015,4,1]],"date-time":"2015-04-01T00:00:00Z","timestamp":1427846400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antivir Chem Chemother"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> Aqueous solubilities of prodrugs were improved, oxidation of prodrugs by animal cytosols occurred in\u00a0vitro, and oral absorption of the optimal prodrug sacrovir\u2122 (6-deoxy- mCF<jats:sub>3<\/jats:sub>PG) in the presence of the aqueous adjuvant Soluplus\u00ae and conversion to active compound N<jats:sup>2<\/jats:sup>-[3-(trifluoromethyl)pheny])guanine ( mCF<jats:sub>3<\/jats:sub>PG) were accomplished in mice. Treatment of herpes simplex virus-1 latent mice with sacrovir\u2122 in 1% Soluplus in drinking water significantly suppressed herpes simplex virus-1 reactivation and viral genomic replication. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p> Ad libitum oral delivery of sacrovir\u2122 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\u00a0vivo. <\/jats:p><\/jats:sec>","DOI":"10.1177\/2040206615608722","type":"journal-article","created":{"date-parts":[[2015,10,14]],"date-time":"2015-10-14T01:48:29Z","timestamp":1444787309000},"page":"47-55","update-policy":"http:\/\/dx.doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Prodrugs of herpes simplex thymidine kinase inhibitors"],"prefix":"10.1177","volume":"24","author":[{"given":"Milka","family":"Yanachkova","sequence":"first","affiliation":[{"name":"GLSynthesis Inc. One Innovation Drive, Worcester, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Chu","family":"Xu","sequence":"additional","affiliation":[{"name":"GLSynthesis Inc. One Innovation Drive, Worcester, USA"},{"name":"Yancheng Tianhai Pharma Inc., Yancheng, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofya","family":"Dvoskin","sequence":"additional","affiliation":[{"name":"GLSynthesis Inc. One Innovation Drive, Worcester, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward J","family":"Dix","sequence":"additional","affiliation":[{"name":"GLSynthesis Inc. One Innovation Drive, Worcester, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan B","family":"Yanachkov","sequence":"additional","affiliation":[{"name":"GLSynthesis Inc. One Innovation Drive, Worcester, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Focher","sequence":"additional","affiliation":[{"name":"Istituto di Genetica Molecolare, Consiglio Nazionalle delle Ricerche, Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lida","family":"Savi","sequence":"additional","affiliation":[{"name":"Istituto di Genetica Molecolare, Consiglio Nazionalle delle Ricerche, Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M Dulfary","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA"},{"name":"Department of Ophthalmology, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA"},{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy P","family":"Foster","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA"},{"name":"Department of Ophthalmology, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA"},{"name":"Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, School of Medicine, New Orleans, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George E","family":"Wright","sequence":"additional","affiliation":[{"name":"GLSynthesis Inc. 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