Antiviral Chemistry and Chemotherapy最新文献

{"title":"Novel symmetrical phenylenediamines as potential anti-hepatitis C virus agents","authors":"Marcella Bassetto, S. Ferla, P. Leyssen, J. Neyts, Mark M Yerukhimovich, D. Frick, Rachel O'Donnell, A. Brancale","doi":"10.1177/2040206616676353","DOIUrl":"https://doi.org/10.1177/2040206616676353","url":null,"abstract":"Background Despite the great progress made in the last 10 years, alternative strategies might help improving definitive treatment options against hepatitis C virus infection. Methods With the aim of identifying novel inhibitors of the hepatitis C virus-1b replication targeting the viral NS3 helicase, the structures of previously reported symmetrical inhibitors of this enzyme were rationally modified, and according to docking-based studies, four novel scaffolds were selected for synthesis and evaluation in the hepatitis C virus-1b subgenomic replicon assay. Results Among the newly designed compounds, one new structural family was found to inhibit the hepatitis C virus-1b replication in the micromolar range. This scaffold was chosen for further exploration and different novel analogues were synthesised and evaluated. Conclusions Different new inhibitors of the hepatitis C virus genotype 1b replication were identified. Some of the new compounds show mild inhibition of the NS3 helicase enzyme.","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"38 1","pages":"155 - 160"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83617133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular basis of influenza hemagglutinin inhibition with an entry-blocker peptide by computational docking and mass spectrometry","authors":"R. Lu, P. Müller, K. Downard","doi":"10.1177/2040206615622920","DOIUrl":"https://doi.org/10.1177/2040206615622920","url":null,"abstract":"Background The increased resistance of circulating strains to current antiviral inhibitors of the influenza virus necessitates that new antivirals and their mode of action are identified. Influenza hemagglutinin is an ideal target given inhibitors of its function can block the entry of the virus into host cells during the early stages of replication. This article describes the molecular basis for the inhibition of H1 and H5 hemagglutinin by an entry-blocker peptide using companion molecular docking and mass spectrometry-based experiments. Methods A combination of hemagglutination inhibition assays, computational molecular docking and a novel mass spectrometry-based approach are employed to explore the mode of action of the entry-blocker peptide at a molecular level. Results The entry-blocker peptide is shown to be able to maximally inhibit blood cell hemagglutination at a concentration of between 6.4 and 9.2 µM. The molecular basis for this inhibition is derived from the binding of the peptide to hemagglutinin in the vicinity of the reported sialic acid binding site surrounded by an α-helix (190-helix) and two loop (130-loop and 220-loop) regions in the case of a H1 hemagglutinin and the second loop region in the case of a H5 hemagglutinin. Conclusions The results support the recognized potential of the entry-blocker peptide as an effective antiviral agent that can inhibit the early stages of viral replication and further illustrate the power of a combination of docking and a mass spectrometry approach to screen the molecular basis of new antiviral inhibitors to the influenza virus.","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"46 1","pages":"109 - 117"},"PeriodicalIF":0.0,"publicationDate":"2015-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82234865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Derivatives of usnic acid inhibit broad range of influenza viruses and protect mice from lethal influenza infection","authors":"A. Shtro, V. Zarubaev, OA Luzina, DN Sokolov, N. Salakhutdinov","doi":"10.1177/2040206616636992","DOIUrl":"https://doi.org/10.1177/2040206616636992","url":null,"abstract":"Background Influenza is a disease of significant morbidity and mortality, the number of anti-influenza drugs is small; many of them stimulate the appearance of resistant strains. In this work, we demonstrate activity of some usnic acid (UA) derivatives against influenza virus in vitro and in vivo. Methods Organic synthesis was used to prepare compounds. Antiviral activity of the compounds in vitro was evaluated by their ability to decrease the virus titer on Madin–Darby Canine Kidney cells. In vivo activity was evaluated by decrease of mortality and index of protection. Results Compounds were tested against a broad spectrum of influenza virus strains and showed activity against all used strains. One compound, [5] (valine enamine of UA), also significantly reduced lethality of infected animals and does not give rise to the appearance of resistant strains. Additional studies showed that hepatotoxicity of compound [5] is reduced comparatively to UA. Conclusion Our results suggest that valine enamine of UA could be a potential candidate for the development of a new anti-influenza therapy.","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"57 1","pages":"92 - 98"},"PeriodicalIF":0.0,"publicationDate":"2015-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80328560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin decreases brain apoptosis, oxidative stress, and CD200 expression and increased survival rate in mice infected by Venezuelan equine encephalitis virus.","authors":"Milagros Montiel,&nbsp;Ernesto Bonilla,&nbsp;Nereida Valero,&nbsp;Jesús Mosquera,&nbsp;Luz M Espina,&nbsp;Yasmir Quiroz,&nbsp;Melchor Álvarez-Mon","doi":"10.1177/2040206616660851","DOIUrl":"https://doi.org/10.1177/2040206616660851","url":null,"abstract":"<p><strong>Background: </strong>Pro-inflammatory and oxidative events during brain Venezuelan equine encephalitis virus infection could lead to apoptosis and induce anti-inflammatory responses (increased expression of CD200). The aim of this study was to determine the effect of melatonin on brain apoptosis, oxidative stress, and CD200 molecule in mice and neuroblastoma cultures infected by Venezuelan equine encephalitis virus.</p><p><strong>Methods: </strong>Mice were infected with 10 median lethal doses (LD50) of Venezuelan equine encephalitis virus, treated with melatonin (500 µg/kg bw; three days before infection and during all experimental time) and sacrificed on days 1, 3, and 5 postinfection. Brain samples were obtained at those periods of time. In addition, infected neuroblastoma cell cultures (multiplicity of infection [MOI]: 1) were treated with 0, 0.1, 0.5, and 1 mM of melatonin and analyzed at 2, 4, and 6 h. CD200 and apoptosis expressions were analyzed by immunohistochemistry and TUNEL assay, respectively. Nitrites and malondialdehyde were determined by appropriate biochemical methods.</p><p><strong>Results: </strong>Increased brain expression of apoptosis, nitrite, and malondialdehyde productions and CD200 of infected mice were found. Melatonin diminished those expressions. Similarly, high apoptosis expression and nitrite and malondialdehyde productions on infected neuroblastoma cultures were diminished by melatonin. Melatonin increased the survival rate (25%) in Venezuelan equine encephalitis virus-infected animals compared with untreated infected mice (0%).</p><p><strong>Conclusions: </strong>Neurological damage during brain Venezuelan equine encephalitis virus infection could be mediated by apoptosis and oxidative stress and CD200 molecule could be an important anti-inflammatory response. Melatonin could be beneficial reducing apoptosis and oxidative stress.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"24 3-4","pages":"99-108"},"PeriodicalIF":0.0,"publicationDate":"2015-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206616660851","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34646237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Zika virus structural biology: Challenges and opportunities for intervention.","authors":"Bryan D Cox,&nbsp;Richard A Stanton,&nbsp;Raymond F Schinazi","doi":"10.1177/2040206616653873","DOIUrl":"https://doi.org/10.1177/2040206616653873","url":null,"abstract":"<p><strong>Background: </strong>Zika virus is an emerging crisis as infection is implicated in severe neurological disorders-Guillain-Barré syndrome and fetal microcephaly. There are currently no treatment options available for Zika virus infection. This virus is part of the flavivirus genus and closely related to Dengue Fever Virus, West Nile Virus, and Japanese Encephalitis Virus. Like other flaviviruses, the Zika virus genome encodes three structural proteins (capsid, precursor membrane, and envelope) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Currently, no structural information exists on these viral proteins to facilitate vaccine design and rational drug discovery.</p><p><strong>Methods: </strong>Structures for all Zika virus viral proteins were predicted using experimental templates available from closely related viruses using the online SwissModel server. These homology models were compared to drug targets from other viruses using Visual Molecular Dynamics Multiseq software. Sequential alignment of all Zika virus polyproteins was performed using Clustal Omega to identify mutations in specific viral proteins implicated in pathogenesis.</p><p><strong>Results: </strong>The precursor membrane, envelope, and NS1 proteins are unique to Zika virus highlighting possible challenges in vaccine design. Sequential differences between Zika virus strains occur at critical positions on precursor membrane, envelope, NS2A, NS3, NS4B, and NS5 as potential loci for differential pathogenesis. Druggable pockets in Dengue Fever Virus and West Nile Virus NS3 and NS5 are retained in predicted Zika virus structures.</p><p><strong>Conclusions: </strong>Lead candidates for Zika virus can likely be established using NS3 and NS5 inhibitors from other flaviviruses, and the structures presented can provide opportunities for Zika virus intervention strategies.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"24 3-4","pages":"118-26"},"PeriodicalIF":0.0,"publicationDate":"2015-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206616653873","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34572997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination activity of neuraminidase inhibitor oseltamivir and α-tocopherol in influenza virus A (H3N2) infection in mice.","authors":"Angel S Galabov,&nbsp;Milka Mileva,&nbsp;Lora Simeonova,&nbsp;Galina Gegova","doi":"10.1177/2040206616656263","DOIUrl":"https://doi.org/10.1177/2040206616656263","url":null,"abstract":"<p><strong>Background: </strong>Influenza is a highly contagious viral infection of the respiratory system. To attack two processes involved in flu pathogenesis-viral replication in the infected body and oxidative damages, we studied the combination effect of neuraminidase inhibitor oseltamivir and antioxidant α-tocopherol in experimental model of influenza.</p><p><strong>Methods: </strong>After inoculation of albino mice with 10 MLD50 (50% mouse lethal dose) of influenza virus A/Aichi/2/68 (H3N2), oseltamivir was applied orally at three doses, 2.5 mg/kg, 1.25 mg/kg, and 0.625 mg/kg, for five days post infection. α-Tocopherol (120 mg/kg, in sunflower oil) was administered intraperitoneally. Three schemes of α-tocopherol five-day course were tested: onset five or two days before infection, or on the virus inoculation day.</p><p><strong>Results: </strong>Strongly dose-dependent augmented antiviral effect of the combination α-tocopherol and 0.625 mg/kg oseltamivir was demonstrated when α-tocopherol was administered simultaneously with oseltamivir: a pronounced decrease in mortality rate (a 78% protection), and a lengthening of mean survival time by 3.2-4 days. Lung parameters showed a substantial decrease in infectious virus content (Δ logs = 3.8/4.1) and a marked diminishment of lung index and pathology. Combination α-tocopherol with 1.25 mg/kg oseltamivir manifested a marked protective effect, but the effect on lung parameters was less. The combination effect of α-tocopherol with 2.5 mg/kg oseltamivir did not surpass the monotherapeutic effect of oseltamivir. When α-tocopherol was applied in courses starting five or two days before infection, its combination with oseltamivir was ineffective.</p><p><strong>Conclusions: </strong>Evidently, α-tocopherol could be considered as prospective component of influenza therapy in combination with oseltamivir.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"24 3-4","pages":"83-91"},"PeriodicalIF":0.0,"publicationDate":"2015-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206616656263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34608777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and anti-HIV-1 activity of 1-substituted 3-(3,5-dimethylbenzyl)triazine derivatives.","authors":"Norikazu Sakakibara,&nbsp;Gianfranco Balboni,&nbsp;Cenzo Congiu,&nbsp;Valentina Onnis,&nbsp;Yosuke Demizu,&nbsp;Takashi Misawa,&nbsp;Masaaki Kurihara,&nbsp;Yoshihisa Kato,&nbsp;Tokumi Maruyama,&nbsp;Masaaki Toyama,&nbsp;Mika Okamoto,&nbsp;Masanori Baba","doi":"10.1177/2040206615612208","DOIUrl":"https://doi.org/10.1177/2040206615612208","url":null,"abstract":"<p><strong>Background: </strong>The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an attractive target for the development of drugs used in the treatment of HIV-1 infection and acquired immune deficiency syndrome (AIDS). We have continued the search for novel anti-HIV-1 agents using the structure-activity relationships of the successful 1,3-disubstituted and 1,3,6-trisubstituted uracil-type HIV-1 RT inhibitors.</p><p><strong>Methods: </strong>A series of new triazine analogs were synthesized using an established method. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cytotoxicity of the compounds was evaluated by assessing the viability of mock-infected cells.</p><p><strong>Results: </strong>Some of the compounds showed good-to-moderate activities against HIV-1, with half-maximal effective concentrations (EC50) in the submicromolar range. In particular, a dihydro-1-(4-aminobenzyl)triazine analog showed satisfactory anti-HIV-1 activity with an EC50 of 0.110 µM and a selectivity index (SI) of 909. Furthermore, molecular modeling analyses were performed to explore the major interactions between HIV-1 RT and potent inhibitors. These results may be important for further development of this class of compounds as anti-HIV-1 agents.</p><p><strong>Conclusion: </strong>The satisfactory anti-HIV-1 activity of triazine analogs may serve as the basis for further investigations of the behavior of this class of compounds against drug-resistant mutants.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"24 2","pages":"62-71"},"PeriodicalIF":0.0,"publicationDate":"2015-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206615612208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34300047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice.","authors":"Michael T Eadon,&nbsp;Hongji Zhang,&nbsp;Todd C Skaar,&nbsp;Takashi Hato,&nbsp;Pierre C Dagher,&nbsp;Samir K Gupta,&nbsp;Zeruesenay Desta","doi":"10.1177/2040206615595318","DOIUrl":"https://doi.org/10.1177/2040206615595318","url":null,"abstract":"<p><strong>Background: </strong>The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration. We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of high-dose integrase inhibitors.</p><p><strong>Methods: </strong>C57BL/6 mice were fed standard water (CTRL, n = 6), raltegravir-containing water (40 mg/kg/day, n = 6), or dolutegravir-containing water (2.7 mg/kg/day, n = 6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen.</p><p><strong>Results: </strong>The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p < 0.05) compared to control (raltegravir = 0.25 mg/dl, dolutegravir = 0.30 mg/dl versus CTRL = 0.17 mg/dl). Blood urea nitrogen, cystatin C, and urine microalbumin were unchanged. Kidney injury molecule-1 tissue expression in raltegravir and dolutegravir groups was nonsignificantly elevated compared to control (1.2-fold compared to control). Renal histopathology by periodic acid-Schiff staining failed to reveal glomerular or tubular renal injury in any group.</p><p><strong>Conclusion: </strong>These studies are consistent with integrase inhibitors competitively inhibiting creatinine secretion. While no evidence of direct nephrotoxicity was observed after two weeks of high-dose drug administration, additional studies may be performed to understand whether these drugs lead to chronic nephropathy.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"24 2","pages":"72-6"},"PeriodicalIF":0.0,"publicationDate":"2015-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206615595318","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33884039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of the anti-enterovirus activity of a series of pleconaril/pirodavir-like compounds.","authors":"Angela Bernard,&nbsp;Céline Lacroix,&nbsp;Maria G Cabiddu,&nbsp;Johan Neyts,&nbsp;Pieter Leyssen,&nbsp;Raffaello Pompei","doi":"10.1177/2040206615589035","DOIUrl":"https://doi.org/10.1177/2040206615589035","url":null,"abstract":"<p><strong>Background: </strong>The Enterovirus genus of the Picornaviridae is represented by several viral pathogens that are associated with human disease, namely Poliovirus 1, Enterovirus 71 and Rhinoviruses. Enterovirus 71 has been associated with encephalitis, while Rhinoviruses are a major cause of asthma exacerbations and chronic obstructive pulmonary disease. Based on the structure of both pleconaril and pirodavir, we previously synthesized some original compounds as potential inhibitors of Rhinovirus replication.</p><p><strong>Methods: </strong>These compounds were explored for in vitro antiviral potential on other human pathogenic Enteroviruses, namely Enterovirus 71 on rhabdo-myosarcoma cells, Coxsackievirus B3 on Vero cells, Poliovirus 1 and Echovirus 11 on BGM cells.</p><p><strong>Results: </strong>Activity was confirmed for compound against Rhinovirus 14. Furthermore, few compounds showed a cell-protective effect on Enterovirus 71, presented a marked improvement as compared to the reference drug pleconaril for inhibitory activity on both Enterovirus 71 and Poliovirus 1. The most striking observation was the clear cell protective effect for the set of analogues in a virus-cell-based assay for Echovirus 11 with an effective concentration (EC50) as low as 0.3 µM (Selectivity index or SI = 483), and selectivity indexes greater than 857 (EC50 = 0.6 µM) and 1524 (EC50 = 0.33 µM).</p><p><strong>Conclusion: </strong>Some of the evaluated compounds showed potent and selective antiviral activity against several enterovirus species, such as Enterovirus 71 (EV-A), Echovirus 11 (EV-B), and Poliovirus 1 (EV-C). This could be used as a starting point for the development of other pleconaril/pirodavir-like enterovirus inhibitors with broad-spectrum activity and improved effects as compared to the reference drugs.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"24 2","pages":"56-61"},"PeriodicalIF":0.0,"publicationDate":"2015-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206615589035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33385343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prodrugs of herpes simplex thymidine kinase inhibitors.","authors":"Milka Yanachkova,&nbsp;Wei-Chu Xu,&nbsp;Sofya Dvoskin,&nbsp;Edward J Dix,&nbsp;Ivan B Yanachkov,&nbsp;Federico Focher,&nbsp;Lida Savi,&nbsp;M Dulfary Sanchez,&nbsp;Timothy P Foster,&nbsp;George E Wright","doi":"10.1177/2040206615608722","DOIUrl":"https://doi.org/10.1177/2040206615608722","url":null,"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.","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"24 2","pages":"47-55"},"PeriodicalIF":0.0,"publicationDate":"2015-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206615608722","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34151814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}