Antiviral Chemistry and Chemotherapy最新文献

{"title":"Cycluridine: A novel antiviral effective against flaviviruses.","authors":"Angel S Galabov,&nbsp;Lucia Mukova,&nbsp;Yuriy P Abashev,&nbsp;Lilia Wassilewa,&nbsp;Petko Tzvetkov,&nbsp;Vassil Minkov,&nbsp;Igor F Barinskiy,&nbsp;Charles M Rice,&nbsp;Sergey Ouzounov,&nbsp;Dorotea Sidzhakova","doi":"10.1177/2040206617723442","DOIUrl":"https://doi.org/10.1177/2040206617723442","url":null,"abstract":"<p><p>This review describes the contemporary state of research for antivirals effective against flaviviruses, especially focusing on inhibitors of the pestivirus causative agent of bovine viral diarrhoea virus. We highlight cycluridine, an originally synthesized Mannich's base [a tetrahydro-2(1H)-pyrimidinones derivative], as a highly effective antiviral possessing a strong inhibitory effect on bovine viral diarrhoea virus replication. Cycluridine was active against replication of a wide variety of bovine viral diarrhoea virus strains in cell cultures. The drug-sensitive period in the bovine viral diarrhoea virus replication cycle included the latent period and the exponential phase; a 90-min delay in the peak of viral RNA synthesis was observed. Cycluridine administered orally manifested a pronounced protective effect in calves with natural mucosal disease/viral diarrhoea and calves experimentally infected with bovine viral diarrhoea virus. Its magnitude of activity and selectivity places cycluridine in the lead among all known substances with anti- bovine viral diarrhoea virus activity. Additionally, cycluridine applied subcutaneously showed anti-tick-born encephalitis virus activity, manifesting a marked protective effect in mice infected with tick-born encephalitis virus. Cycluridine could be a prospective antiviral in veterinary and medical practice for the treatment of bovine viral diarrhoea virus and other flavivirus infections.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"25 2","pages":"58-67"},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206617723442","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35237816","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":"Editorial.","authors":"Andrea Brancale","doi":"10.1177/2040206617724304","DOIUrl":"https://doi.org/10.1177/2040206617724304","url":null,"abstract":"Last May, the International Society for Antiviral Research (ISAR) held the 30th International Conference on Antiviral research in Atlanta, Georgia, USA. This is one of the most important international meetings in our research field and it attracts scientists from different scientific backgrounds, from chemistry to biology. ISAR is the premier international organization completely dedicated to antiviral research and Antiviral Chemistry and Chemotherapy is proud to be one of the society’s official journals. Our aim is to consolidate this relationship in the next few years and to explore new opportunities to work closely together. Indeed, in Atlanta, we have offered an open access fees waiver to the winner of the Young Researcher poster award. This recognizes the effort of AVCC, echoed by ISAR, in supporting early stage researchers in a crucial moment of their career, when they are building their international profile. We believe that through these kinds of initiatives, we can increase our visibility and reputation in the antiviral research community and, at the same time, do what we do best: helping the scientists in the field to make their work visible and accessible. We will continue to offer the publication fees waiver as part of the ISAR Young investigator Poster award in the future and we will keep working with ISAR to further expand our collaboration. Following up on the support for early stage researcher, AVCC is always very keen to engage with them and involve them in our activities. Acting as Guest Editor in one of our Special Collections, for example, can provide the young scientists with a new experience and insight in the editorial world. Indeed, our initial collections will be edited by three very bright rising stars in the antiviral field: Jerome Deval, Joana Duarte and Giuseppe La Regina. We are now planning a new series of Special Collections and we are looking for new potential Guest Editors. For this reason, we would be very happy to hear your ideas and if you think you would be interested in acting as editor, do not hesitate in contacting us. Finally, I will now leave you to what AVCC is really about: the science. We have some very interesting paper just published in this issue and I strongly encourage you to read them and share them with your colleagues.","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"25 2","pages":"19"},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206617724304","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35237814","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":"Metabolic reprogramming during hepatitis B disease progression offers novel diagnostic and therapeutic opportunities.","authors":"Jesse Jr Masson,&nbsp;Hugh Ww Billings,&nbsp;Clovis S Palmer","doi":"10.1177/2040206617701372","DOIUrl":"https://doi.org/10.1177/2040206617701372","url":null,"abstract":"<p><p>Metabolic remodeling occurs in immune cells during an infection. Host cells must upregulate energy production for growth, proliferation, and effector functions to limit the damage imposed by pathogens. One example, the hepatitis B virus, induces hepatic injury in human hepatocytes through dysregulation of aerobic glycolysis and lipid metabolism. Increased glycolytic metabolism mediated by elevated expression of Glut1, glucose influx, and lactate secretion is associated with this Warburg phenotype, a classic metabolic signature also observed in cancer cells. This article brings into focus the tight interaction between HBV infection and metabolic dysfunction and how these processes facilitate the progression of end-stage liver diseases, such as hepatocellular carcinoma. We also provide evidence and models by which other viruses such as HIV and Zika disrupt their host metabolic machinery. The emergence of the immunometabolism field provides novel opportunities to take advantage of intermediary metabolites and key metabolic pathways for diagnostic and therapeutic purposes.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"25 2","pages":"53-57"},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206617701372","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35237813","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":"Editorial for AVCC relaunch issue.","authors":"Andrea Brancale","doi":"10.1177/2040206617704930","DOIUrl":"https://doi.org/10.1177/2040206617704930","url":null,"abstract":"In 1990, when Antiviral Chemistry and Chemotherapy was originally launched, the Editors recognised the challenges and the promises of a research field that was rapidly expanding. With this in mind, they decided to create a new journal that could be ‘at the centre of this excitement’. Since then, the antiviral research field has grown significantly, fostering some remarkable successes along the way: HAART has transformed a HIV infection from an almost certain death sentence into a manageable disease and a cure for all HCV-infected patients is within our grasp. Yet, many challenges still remain. Emerging and re-emerging viruses like Zika or Cikungunya have often appeared in the mainstream news in the last few years, while no antiviral treatments for viral infections such as Dengue are yet available. For this reason, we believe the new Antiviral Chemistry and Chemotherapy, relaunched with this issue, has still an important role to play by supporting researchers in sharing their work and ideas in a research field that is still exciting as it was almost three decades ago. Our renewed journal will focus entirely on publishing excellent, reproducible science. This is our most important aim. We recognise that antiviral research is a highly multidisciplinary field and we welcome papers from all scientific backgrounds, from chemistry to basic virology. What we can offer is a fast and competent peer review, and a fast publication, thanks to an incredibly talented group of Editors and an enthusiastic Editorial Board. In addition to original research papers, we will encourage submission of review articles and pointers. We will also regularly publish special issues completely dedicated to particularly interesting and timely topics. Finally, it is important to point out that Antiviral Chemistry and Chemotherapy is now an Open Access journal. We strongly believe that this is the best publishing method for a journal that has the ambition of becoming again an important reference point in the antiviral field. Open Access also offers clear benefits to our authors. For example, it has been suggested that openly accessible papers are cited more frequently than papers published on subscription journals. Furthermore, several funding bodies now require that the results obtained from the research they supported should be publicly available. In conclusion, Antiviral Chemistry and Chemotherapy is ready to start again and to regain its role in assisting fellow scientist in spreading their ideas and novel scientific results. We have plenty to offer to the antiviral community and we invite you to be part of this new exciting endeavour.","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"25 1","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206617704930","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34920648","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":"Combinations of L-N^G-monomethyl-arginine and oseltamivir against pandemic influenza A virus infections in mice.","authors":"Donald F Smee,&nbsp;Ashley Dagley,&nbsp;E B Tarbet","doi":"10.1177/2040206617691885","DOIUrl":"https://doi.org/10.1177/2040206617691885","url":null,"abstract":"<p><p>L-N^G-monomethyl-arginine (L-NMMA) is an experimental compound that suppresses nitric oxide production in animals. The compound was combined with oseltamivir to treat lethal influenza A/California/04/2009 (H1N1) pandemic virus infections in mice. Treatments were given twice a day for five days starting 4 h (oseltamivir, by oral gavage) or three days (L-NMMA, by intraperitoneal route; corresponding to the time previously reported for nitric oxide induction in the animals) after infection. Low doses of oseltamivir were used in order to demonstrate synergy or antagonism. Oseltamivir monotherapy protected 70% of mice from death at 1 mg/kg/day. L-NMMA (40 and 80 mg/kg/day) was ineffective alone in preventing mortality. Compared to oseltamivir treatment alone, L-NMMA combined with oseltamivir was synergistically effective (as evaluated by three-dimensional MacSynergy analysis), resulting in survival increases from 20 to 70% when 40 or 80 mg/kg/day of L-NMMA was combined with 0.3 mg/kg/day of oseltamivir, and from 70 to 100% survival increases when these doses were combined with 1 mg/kg/day of oseltamivir. These data demonstrate that a nitric oxide inhibitor such as L-NMMA has the potential to be beneficial when combined with oseltamivir in treating influenza virus infections.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"25 1","pages":"11-17"},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206617691885","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34920645","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":"Equilibrative nucleoside transporter 1 expression in primary human hepatocytes is highly variable and determines uptake of ribavirin.","authors":"Kanwal Baloch,&nbsp;Liqiong Chen,&nbsp;Ameer A Memon,&nbsp;Laura Dexter,&nbsp;William Irving,&nbsp;Mohammad Ilyas,&nbsp;Brian J Thomson","doi":"10.1177/2040206616686894","DOIUrl":"https://doi.org/10.1177/2040206616686894","url":null,"abstract":"<p><p>Aims Ribavirin is a nucleoside analogue and remains a necessary component of both interferon-based and directly acting anti-viral regimens for the treatment of hepatitis C virus infection. The achievable concentration of ribavirin within hepatocytes is likely to be an important determinant of therapeutic outcome. In vitro expression levels of equilibrative nucleoside transporter 1 (ENT1) has been shown to be a predictor of treatment response in patients receiving nucleoside-based chemotherapeutic agents. We therefore investigated whether a similar relationship existed between ENT1 expression and ribavirin uptake in freshly isolated primary hepatocytes. Methods Primary hepatocytes were cultured on collagen-coated plates and exposed to ribavirin. Parallel samples were taken for high-performance liquid chromatography to assess ribavirin uptake and for quantitative polymerase chain reaction to evaluate ENT1 expression. Similar assays were performed on the human hepatoma cell line (Huh7). ENT1 gene sequence was analysed by cloning of polymerase chain reaction amplified complementary DNA followed by direct sequencing. Results There was a strong direct correlation between expression of ENT1 in primary hepatocytes and ribavirin uptake at 24 hr. Huh7 cells expressed ENT1 at similar levels to the majority of primary hepatocytes, but did not take up ribavirin. Sequencing revealed that ENT1 in Huh7 cells is wild type. Conclusions In this study, we clearly demonstrate that ribavirin uptake in primary human hepatocytes is variable and correlates with ENT1 expression. This variation in ENT1 expression may account for differences in response rate in patients receiving ribavirin-based anti-hepatitis C virus therapy.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"25 1","pages":"2-10"},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206616686894","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34920646","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":"Synthesis of multi ring-fused imidazo [1,2- a]isoquinoline-based fluorescent scaffold as anti-Herpetic agent.","authors":"Harapriya Chakravarty,&nbsp;Durbadal Ojha,&nbsp;Ananda K Konreddy,&nbsp;Chandralata Bal,&nbsp;Nidhi S Chandra,&nbsp;Ashoke Sharon,&nbsp;Debprasad Chattopadhyay","doi":"10.1177/2040206616680968","DOIUrl":"https://doi.org/10.1177/2040206616680968","url":null,"abstract":"<p><strong>Background: </strong>Natural product-inspired synthesis is a key incorporation in modern diversity-oriented synthesis to yield biologically novel scaffold. Inspired by β-carboline fused system, we have designed molecules with multi ring fused scaffold by modifying the tricyclic pyrido[3,4- b]indole ring with imidazo[1,2- a]isoquinoline.</p><p><strong>Methods: </strong>A highly convergent approach with new C-N and C-C bond formation to synthesize multiring fused complex scaffold imidazo[1,2- a]isoquinolinies as fluorophores. N-nucleophile-induced ring transformation of 2 H-pyran-2-one followed by in situ cis-stilbene-type oxidative photocyclization yielded new C-C bond formation without additional oxidant. The cytotoxicity, effective concentrations, and the mode of action of the synthesized analogs were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),, plaque reduction, time of addition, and reverse transcriptase Polymerase Chain Reaction (PCR).</p><p><strong>Results: </strong>Novel imidazo[1,2- a]isoquinoline analogs were prepared, and the results revealed that trans isomer of cyclopropyl analog (EC₅₀ 35 and 37.5 µg/ml) and trans isomer of citric acid salt of phenyl analog (EC₅₀ 38.2 and 39.8 µg/ml) possess significant anti-Herpes Simplex Virus (HSV) activity with selectivity index of >10. The kinetic study demonstrated that both the analogs inhibited HSV-1F and HSV-2G at 2-4 h postinfection. Finally, western blot and reverse transcriptase PCR assays revealed that both the analogs suppressed viral immediate early transcription.</p><p><strong>Conclusion: </strong>Novel imidazo[1,2- a]isoquinoline analogs were synthesized from pyranone with appropriate amines. Two compounds showed better antiviral profile on HSV-infected Vero cells, compared to the standard drug acyclovir (ACV). Overall, we discovered a promising scaffold to develop a nonnucleoside lead targeting the viral immediate early transcription for the management of HSV infections.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"24 5-6","pages":"127-135"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206616680968","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37071773","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":"Effect of sialidase fusion protein (DAS 181) on human metapneumovirus infection of Hep-2 cells","authors":"Sutthiwan Thammawat, T. Sadlon, P. Adamson, D. Gordon","doi":"10.1177/2040206616665971","DOIUrl":"https://doi.org/10.1177/2040206616665971","url":null,"abstract":"Human metapneumovirus is an emerging cause of lower respiratory disease in infants, young children, and immunocompromised adults. We have previously demonstrated that human metapneumovirus infection is mediated by interaction of human metapneumovirus attachment (G) and/or fusion (F) proteins with cellular glycosaminoglycans. We report here the activity of an investigational sialidase fusion protein, DAS181, on human metapneumovirus infection of Hep-2 cells. These results suggest that human metapneumovirus infection may involve sialic acids, providing a new therapeutic strategy for human metapneumovirus for which there is currently no available treatment. Methods Hep-2 cells were preincubated with DAS181 or control DAS185 (a mutated sialidase) prior to inoculation with human metapneumovirus strains. Infectivity was assessed by a cell-based ELISA quantitating human metapneumovirus matrix protein. The effect of DAS181 on binding of recombinant G attachment protein was also determined. Results DAS181 blocked infection of human metapneumovirus strains A2, B1, and B2 at low concentrations. No effect of DAS185 was observed. Binding of MPV G protein to Hep-2 cells was also markedly inhibited by preincubation of cells with DAS181. Conclusions These results suggest that human metapneumovirus may utilize sialic acids as an entry cofactor. DAS181 may thus represent a new therapeutic agent useful for the treatment of human metapneumovirus.","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"35 1","pages":"161 - 165"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85522877","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":"Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative.","authors":"Wataru Ito,&nbsp;Masaaki Toyama,&nbsp;Mika Okamoto,&nbsp;Masanori Ikeda,&nbsp;Koichi Watashi,&nbsp;Takaji Wakita,&nbsp;Yuichi Hashimoto,&nbsp;Masanori Baba","doi":"10.1177/2040206616663956","DOIUrl":"https://doi.org/10.1177/2040206616663956","url":null,"abstract":"<p><strong>Background: </strong>The novel phenanthridinone derivative HA-719 has recently been identified as a highly potent and selective inhibitor of hepatitis C virus replication. To elucidate its mechanism of inhibition, we have isolated and analyzed a clone of hepatitis C virus replicon cells resistant to HA-719.</p><p><strong>Methods: </strong>To isolate HA-719-resistant replicon cells, Huh-7 cells containing subgenomic hepatitis C virus replicons (genotype 1b) with a luciferase reporter (LucNeo#2) were cultured in the presence of G418 and escalating concentrations of HA-719. After several passages, total RNA was extracted from the growing cells, and Huh-7 cells were transfected with the extracted RNA. Limiting dilution of the transfected cells was performed to obtain an HA-719-resistant clone.</p><p><strong>Results: </strong>The 50% effective concentration (EC₅₀) of HA-719 for hepatitis C virus replication was 0.058 ± 0.012 µM in LucNeo#2 cells. The replicon cells capable of growing in the presence of G418 and 3 µM HA-719 were obtained after 18 passages (72 days). The HA-719-resistant clone LucNeo719R showed 98.3-fold resistant to the compound (EC₅₀ = 5.66 ± 0.92 µM), but the clone had no cross-resistance to telaprevir (NS3 inhibitor), daclatasvir (NS5A inhibitor), and VX-222 (NS5B inhibitor). The sequence analysis for the wild-type and LucNeo719R identified 3, 2 and 7 mutations in NS3/4 A, NS4B, and NS5A, respectively, but no mutations in NS5B.</p><p><strong>Conclusion: </strong>None of the amino acid mutations in the resistant clone corresponds to those reported to confer drug-resistance to current anti-hepatitis C virus agents, suggesting that the target of HA-719 for hepatitis C virus inhibition differs from those of the existing agents.</p>","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"24 5-6","pages":"148-154"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2040206616663956","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34646239","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":"Anti-enteroviral triple combination of viral replication inhibitors: activity against coxsackievirus B1 neuroinfection in mice","authors":"Adelina Stoyanova, I. Nikolova, G. Pürstinger, G. Dobrikov, V. Dimitrov, S. Philipov, A. Galabov","doi":"10.1177/2040206616671571","DOIUrl":"https://doi.org/10.1177/2040206616671571","url":null,"abstract":"Background Chemotherapy is an important tool for controlling enterovirus infections, but clinically effective anti-enterovirus drugs do not currently exist, mainly due to the development of drug resistance. We investigated the combination effects of enterovirus replication inhibitors in order to limit this process. In previous studies, we showed the efficacy of consecutive alternating administration of the triple combinations disoxaril/guanidine/oxoglaucine and pleconaril/guanidine/oxoglaucine against coxsackievirus B1 infection in newborn mice. Drug sensitivity tests of the viral brain isolates showed that these drug combinations prevented the development of drug resistance. Methods In the current study, we replaced guanidine-HCl with enteroviral RNA synthesis inhibitor MDL-860 to test the effect of a new triple combination—pleconaril/MDL-860/oxoglaucine—applied via consecutive alternating administration in newborn mice infected subcutaneously with 20 MLD50 of coxsackievirus B1. Results The pleconaril/MDL-860/oxoglaucine combination via consecutive alternating administration showed high activity at the 75 mg/kg MDL-860 dose: a protective effect of 50% and a pronounced suppression of brain virus titers. Moreover, along with prevention of drug resistance, a phenomenon of increased drug sensitivity was established. MDL-860 sensitivity in pleconaril/MDL-860/oxoglaucine increased 8.2 times vs. placebo (29 times vs. monotherapy) on day 7 and oxoglaucine sensitivity—4.9 times vs. placebo (by 6.8 times vs. monotherapy) on day 13. As concerns pleconaril, a demonstrable prevention of drug resistance was registered without increase of drug sensitivity. Daily, simultaneous administration of pleconaril/MDL-860/oxoglaucine showed no protective effects and led to a rapid development of drug resistance. Conclusions These results add new support for using consecutive alternating administration treatment courses to achieve clinically effective chemotherapy of enterovirus infections.","PeriodicalId":7960,"journal":{"name":"Antiviral Chemistry and Chemotherapy","volume":"3 1","pages":"136 - 147"},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73058896","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}