40 results on '"Shishido, Takao"'
Search Results
2. β-d-N4-hydroxycytidine, a metabolite of molnupiravir, exhibits in vitro antiviral activity against rabies virus
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Konishi, Kei, Kusakabe, Shinji, Kawaguchi, Nijiho, Shishido, Takao, Ito, Naoto, Harada, Michiko, Inoue, Satoshi, Maeda, Ken, Hall, William W., Orba, Yasuko, Sawa, Hirofumi, Sasaki, Michihito, and Sato, Akihiko
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- 2024
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3. Assessing the fitness of a dual-antiviral drug resistant human influenza virus in the ferret model
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Stannard, Harry L., Mifsud, Edin J., Wildum, Steffen, Brown, Sook Kwan, Koszalka, Paulina, Shishido, Takao, Kojima, Satoshi, Omoto, Shinya, Baba, Keiko, Kuhlbusch, Klaus, Hurt, Aeron C., and Barr, Ian G.
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- 2022
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4. FOUR-WEEK ORAL ADMINISTRATION OF BALOXAVIR MARBOXIL AS AN ANTI-INFLUENZA VIRUS DRUG SHOWS NO TOXICITY IN CHICKENS.
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Miki, Mariko, Obara, Ryo Daniel, Nishimura, Kyohei, Shishido, Takao, Ikenaka, Yoshinori, Oka, Ryoko, Sato, Kenji, Nakayama, Shouta M.M., Kimura, Takashi, Kobayashi, Atsushi, Aoshima, Keisuke, Saito, Keisuke, Hiono, Takahiro, Isoda, Norikazu, and Sakoda, Yoshihiro
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High pathogenicity avian influenza is an acute zoonotic disease with high mortality in birds caused by a high pathogenicity avian influenza virus (HPAIV). Recently, HPAIV has rapidly spread worldwide and has killed many wild birds, including endangered species. Baloxavir marboxil (BXM), an anti-influenza agent used for humans, was reported to reduce mortality and virus secretion from HPAIV-infected chickens (Gallus domesticus, order Galliformes) at a dosage of ≥2.5 mg/kg when administered simultaneously with viral challenge. Application of this treatment to endangered birds requires further information on potential avian-specific toxicity caused by repeated exposure to BXM over the long term. To obtain information of potential avian-specific toxicity, a 4-wk oral repeated-dose study of BXM was conducted in chickens (n = 6 or 7 per group), which are commonly used as laboratory avian species. The study was conducted in reference to the human pharmaceutical guidelines for nonclinical repeated-dose drug toxicity studies to evaluate systemic toxicity and exposure. No adverse changes were observed in any organs examined, and dose proportional increases in systemic exposure to active pharmaceutical ingredients were noted from 12.5 to 62.5 mg/kg per day. BXM showed no toxicity to chickens at doses of up to 62.5 mg/kg per day, at which systemic exposure was approximately 71 times higher than systemic exposure at 2.5 mg/kg, the reported efficacious dosage amount, in HPAIV-infected chickens. These results also suggest that BXM could be considered safe for treating HPAIV-infected endangered birds due to its high safety margin compared with the efficacy dose. The data in this study could contribute to the preservation of endangered birds by using BXM as a means of protecting biodiversity. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial
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Ison, Michael G, Portsmouth, Simon, Yoshida, Yuki, Shishido, Takao, Mitchener, Melissa, Tsuchiya, Kenji, Uehara, Takeki, and Hayden, Frederick G
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- 2020
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6. Prophylactic Treatment with Baloxavir Protects Mice from Lethal Infection with Influenza A and B Viruses.
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Fukao, Keita, Noshi, Takeshi, Shano, Shinya, Baba, Kaoru, Sato, Kenji, Sakuramoto, Masashi, Kitade, Naohisa, Tanioka, Hideki, Kusakabe, Shinji, and Shishido, Takao
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INFLUENZA B virus ,VIRUS diseases ,INFLUENZA viruses ,MICE ,ANTIVIRAL agents ,H2 receptor antagonists - Abstract
Influenza remains a worldwide health concern. Antiviral drugs are considered as one of the useful options for its prevention as a complementary measure to vaccination. Baloxavir acid selectively inhibits the cap-dependent endonuclease of influenza viruses and exhibits marked viral titre reduction in patients. Here, we describe the prophylactic potency of baloxavir acid against lethal infection with influenza A and B viruses in mice. BALB/c mice were subcutaneously administered once with baloxavir acid suspension, or orally administered once daily for 10 days with oseltamivir phosphate solution at human relevant doses. Next, the mice were intranasally inoculated with A/PR/8/34 (H1N1) or B/Hong Kong/5/72 strain at 24 to 96 h after the initial dosing. Prophylactic treatment with the antiviral drugs significantly reduced the lung viral titres and prolonged survival time. In particular, baloxavir acid showed a greater suppressive effect on lung viral titres compared to oseltamivir phosphate. In this model, baloxavir acid maintained significant prophylactic effects against influenza A and B virus infections when the plasma concentration at the time of infection was at least 0.88 and 3.58 ng/mL, respectively. The significant prophylactic efficacy observed in our mouse model suggests the potential utility of baloxavir marboxil for prophylaxis against influenza in humans. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Pharmacokinetic and Pharmacodynamic Analysis of the 3CL Protease Inhibitor Ensitrelvir in a SARS-CoV-2 Infection Mouse Model.
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Fukao, Keita, Nobori, Haruaki, Kuroda, Takayuki, Baba, Kaoru, Matsumoto, Kazumi, Tanaka, Yukari, Tachibana, Yuki, Kato, Teruhisa, and Shishido, Takao
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PROTEASE inhibitors ,SARS-CoV-2 ,LABORATORY mice ,ANIMAL disease models - Abstract
The small-molecule antiviral drug ensitrelvir targets the 3C-like protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study evaluated its inhibitory effect on viral replication in a delayed-treatment mouse model and investigated the relationship between pharmacokinetic (PK) parameters and pharmacodynamic (PD) effects. SARS-CoV-2 gamma-strain-infected BALB/c mice were orally treated with various doses of ensitrelvir starting 24 h post-infection. Effectiveness was determined 48 h after first administration based on lung viral titers. Ensitrelvir PK parameters were estimated from previously reported plasma concentration data and PK/PD analyses were performed. Ensitrelvir doses ≥ 16 mg/kg once daily, ≥8 mg/kg twice daily, or ≥8 mg/kg thrice daily for two days significantly reduced lung viral titers compared to that of the vehicle. PK/PD analyses revealed that mean AUC
0–48h post-first administration, plasma concentration 48 h post-first administration (C48h ), and total time above the target plasma concentration (TimeHigh ) were PK parameters predictive of viral titer reduction. In conclusion, ensitrelvir dose-dependently reduced lung SARS-CoV-2 titers in mice, suggesting it inhibited viral replication. PK parameters C48h and TimeHigh were associated with sustained ensitrelvir plasma concentrations and correlated with the reduced viral titers. The findings suggest that maintaining ensitrelvir plasma concentration is effective for exerting antiviral activity against SARS-CoV-2. [ABSTRACT FROM AUTHOR]- Published
- 2023
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8. Baloxavir Marboxil 2% Granules in Japanese Children With Influenza: An Open-label Phase 3 Study
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Yokoyama, Takato, Sakaguchi, Hiroki, Ishibashi, Toru, Shishido, Takao, Piedra, Pedro A., Sato, Chisako, Tsuchiya, Kenji, and Uehara, Takeki
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- 2020
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9. Antibody dynamics in Japanese paediatric patients with influenza A infection treated with neuraminidase inhibitors in a randomised trial
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Hirotsu, Nobuo, Saisho, Yutaka, Hasegawa, Takahiro, Kitano, Mitsutaka, and Shishido, Takao
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- 2019
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10. Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil
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Taniguchi, Keiichi, Ando, Yoshinori, Nobori, Haruaki, Toba, Shinsuke, Noshi, Takeshi, Kobayashi, Masanori, Kawai, Makoto, Yoshida, Ryu, Sato, Akihiko, Shishido, Takao, Naito, Akira, Matsuno, Keita, Okamatsu, Masatoshi, Sakoda, Yoshihiro, and Kida, Hiroshi
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- 2019
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11. In Vivo Antiviral Activity of Baloxavir against PA/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses.
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Kuroda, Takayuki, Fukao, Keita, Yoshida, Shinpei, Oka, Ryoko, Baba, Kaoru, Ando, Yoshinori, Taniguchi, Keiichi, Noshi, Takeshi, and Shishido, Takao
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INFLUENZA viruses ,SUPERPHOSPHATES ,PLANT viruses ,OSELTAMIVIR ,TITERS ,HAMSTERS - Abstract
Although the prevalence of polymerase acidic (PA)/I38T strains of influenza virus with reduced susceptibility to baloxavir acid is low, there is a possibility of emergence under selective pressure. Furthermore, the virus may be transmitted between humans. We investigated the in vivo efficacy of baloxavir acid and oseltamivir phosphate against influenza A subtypes H1N1, H1N1pdm09, and H3N2, with PA/I38T substitution, at doses simulating human plasma concentrations. A pharmacokinetic/pharmacodynamic analysis was performed to strengthen the validity of the findings and the applicability in a clinical setting. Although the antiviral effect of baloxavir acid was attenuated in mice infected with PA/I38T-substituted viral strains compared with the wild type (WT), baloxavir acid significantly reduced virus titers at higher—but clinically relevant—doses. The virus titer reduction with baloxavir acid (30 mg/kg subcutaneous single dose) was comparable to that of oseltamivir phosphate (5 mg/kg orally twice daily) against H1N1 and H1N1pdm09 PA/I38T strains in mice, as well as the H3N2 PA/I38T strain in hamsters. Baloxavir acid demonstrated an antiviral effect against PA/I38T-substituted strains, at day 6, with no further viral rebound. In conclusion, baloxavir acid demonstrated dose-dependent antiviral effects comparable to that of oseltamivir phosphate, even though the degree of lung virus titer reduction was diminished in animal models infected with PA/I38T-substituted strains. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo.
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Kuroda, Takayuki, Nobori, Haruaki, Fukao, Keita, Baba, Kaoru, Matsumoto, Kazumi, Yoshida, Shinpei, Tanaka, Yukari, Watari, Ryosuke, Oka, Ryoko, Kasai, Yasuyuki, Inoue, Kae, Kawashima, Sho, Shimba, Alice, Hayasaki-Kajiwara, Yoko, Tanimura, Miki, Zhang, Qianhui, Tachibana, Yuki, Kato, Teruhisa, and Shishido, Takao
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PROTEASE inhibitors ,SARS-CoV-2 ,GOLDEN hamster - Abstract
Objectives Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become established in the human population, making the need to develop safe and effective treatments critical. We have developed the small-molecule antiviral ensitrelvir, which targets the 3C-like (3CL) protease of SARS-CoV-2. This study evaluated the in vitro and in vivo efficacy of ensitrelvir compared with that of another SARS-CoV-2 3CL PI, nirmatrelvir. Methods Cultured cells, BALB/cAJcl mice and Syrian hamsters were infected with various SARS-CoV-2 strains, including the ancestral strain WK-521, mouse-adapted SARS-CoV-2 (MA-P10) strain, Delta strain and Omicron strain. Ensitrelvir efficacy was compared with that of nirmatrelvir. Effective concentrations were determined in vitro based on virus-induced cytopathic effects, viral titres and RNA levels. Lung viral titres, nasal turbinate titres, body-weight changes, and animal survival were also monitored. Results Ensitrelvir and nirmatrelvir showed comparable antiviral activity in multiple cell lines. Both ensitrelvir and nirmatrelvir reduced virus levels in the lungs of mice and the nasal turbinates and lungs of hamsters. However, ensitrelvir demonstrated comparable or better in vivo efficacy than that of nirmatrelvir when present at similar or slightly lower unbound-drug plasma concentrations. Conclusions Direct in vitro and in vivo efficacy comparisons of 3CL PIs revealed that ensitrelvir demonstrated comparable in vitro efficacy to that of nirmatrelvir in cell culture and exhibited equal to or greater in vivo efficacy in terms of unbound-drug plasma concentration in both animal models evaluated. The results suggest that ensitrelvir may become an important resource for treating individuals infected with SARS-CoV-2. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil
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Omoto, Shinya, Speranzini, Valentina, Hashimoto, Takashi, Noshi, Takeshi, Yamaguchi, Hiroto, Kawai, Makoto, Kawaguchi, Keiko, Uehara, Takeki, Shishido, Takao, Naito, Akira, and Cusack, Stephen
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- 2018
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14. S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters.
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Sasaki, Michihito, Tabata, Koshiro, Kishimoto, Mai, Itakura, Yukari, Kobayashi, Hiroko, Ariizumi, Takuma, Uemura, Kentaro, Toba, Shinsuke, Kusakabe, Shinji, Maruyama, Yuki, Iida, Shun, Nakajima, Noriko, Suzuki, Tadaki, Yoshida, Shinpei, Nobori, Haruaki, Sanaki, Takao, Kato, Teruhisa, Shishido, Takao, Hall, William W., and Orba, Yasuko
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SARS-CoV-2 ,PROTEASE inhibitors ,COVID-19 ,SARS-CoV-2 Delta variant ,CORONAVIRUS disease treatment ,SARS-CoV-2 Omicron variant - Abstract
In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622 (ensitrelvir), an inhibitor of SARS-CoV-2 main protease (M
pro ; also known as 3C-like protease), decreases viral load and ameliorates disease severity in SARS-CoV-2–infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to submicromolar concentrations in cells. Oral administration of S-217622 demonstrated favorable pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern, including the highly pathogenic Delta variant and the recently emerged Omicron BA.5 and BA.2.75 variants. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase 3 clinical trial (clinical trial registration no. jRCT2031210350), has remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19. A worthwhile antiviral: Despite the success of vaccines and early antivirals in combating the ongoing SARS-CoV-2 pandemic, there remains room for improvement. Here, Sasaki et al. tested the ability of a main protease (Mpro ) inhibitor, S-217622 (ensitrelvir), to protect hamsters from disease after SARS-CoV-2 infection. The authors found that S-217622 retained activity against the Mpro of multiple strains of the virus and reduced disease severity in hamsters when administered orally as a prophylactic or as a therapeutic. Hamsters treated prophylactically with S-217622 did not spread virus to cohoused hamsters. These results support further development of S-217622, which is now under evaluation in a phase 3 clinical trial. [ABSTRACT FROM AUTHOR]- Published
- 2023
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15. Efficacy of ensitrelvir against SARS-CoV-2 in a delayed-treatment mouse model.
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Nobori, Haruaki, Fukao, Keita, Kuroda, Takayuki, Anan, Naomi, Tashima, Ryoichi, Nakashima, Masaaki, Noda, Sayuri, Tajiri, Minako, Torii, Mikinori, Toba, Shinsuke, Uemura, Kentaro, Sanaki, Takao, Shishido, Takao, Tachibana, Yuki, and Kato, Teruhisa
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Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19) and a devastating worldwide health concern. Development of safe and effective treatments is not only important for interventions during the current pandemic, but also for providing general treatment options moving forward. We have developed ensitrelvir, an antiviral compound that targets the 3C-like protease of SARS-CoV-2. In this study, a delayed-treatment mouse model was used to clarify the potential in vivo efficacy of ensitrelvir.Methods: Female BALB/cAJcl mice of different ages were infected with the SARS-CoV-2 gamma strain (hCoV-19/Japan/TY7-501/2021) or mouse-adapted SARS-CoV-2 MA-P10 and then 24 h post-infection orally administered various doses of ensitrelvir or vehicle. Viral titres and RNA levels in the lungs were quantified using VeroE6/TMPRSS2 cells and RT-qPCR, respectively. Body weight loss, survival, lung weight, cytokine/chemokine production, nucleocapsid protein expression and lung pathology were evaluated to investigate the in vivo efficacy of ensitrelvir.Results: Based on infectious viral titres and viral RNA levels in the lungs of infected mice, ensitrelvir reduced viral loads in a dose-dependent manner. The antiviral efficacy correlated with increased survival, reduced body weight loss, reduced pulmonary lesions and suppression of inflammatory cytokine/chemokine levels.Conclusions: This was the first evaluation of the in vivo anti-SARS-CoV-2 efficacy of ensitrelvir in a delayed-treatment mouse model. In this model, ensitrelvir demonstrated high antiviral potential and suppressed lung inflammation and lethality caused by SARS-CoV-2 infection. The findings support the continued clinical development of ensitrelvir as an antiviral agent to treat patients with COVID-19. [ABSTRACT FROM AUTHOR]- Published
- 2022
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16. Gastrin receptor antagonist YM022 prevents hypersecretion after long-term acid suppression
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Nishida, Akito, Kobayashi-Uchida, Ayumi, Akuzawa, Shinobu, Takinami, Yusuke, Shishido, Takao, Kamato, Takeshi, Ito, Hiroyuki, Yamano, Mayumi, Yuki, Hidenobu, Nagakura, Yukinori, Honda, Kazuo, and Miyata, Keiji
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Gastrin -- Physiological aspects ,Omeprazole -- Physiological aspects ,Famotidine -- Physiological aspects ,Gastrointestinal system -- Physiological aspects ,Biological sciences - Abstract
A study was conducted to examine the effect of long-term treatment with omeprazole and famotide, with or without the extremely potent gastrin, YM022, on gastrointestinal function of female rats. The results revealed inhibition of basal and pentagastrin-induced acid secretion two hours after cessation of treatment with YM022 and omeprazole. The effect of famotidine was less significant as compared to omeprazole and controls. Rats showed hyperresponse 14 days after cessation of treatment. These results show that long-term treatment with YM022 increases secretory response to pentagastrin.
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- 1995
17. Acute Parietal and Chief Cell Changes Induced by a Lethal Dose of Lipopolysaccharide in Mouse Stomach before Thrombus Formation
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Ito, Kyoko, Ishida, Katsuhiko, Shishido, Takao, Tabata, Hajime, Miura, Hisaki, Okamiya, Hideaki, and Hanada, Takanori
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- 2000
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18. Evaluating the fitness of PA/I38T-substituted influenza A viruses with reduced baloxavir susceptibility in a competitive mixtures ferret model.
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Lee, Leo YY, Zhou, Jie, Koszalka, Paulina, Frise, Rebecca, Farrukee, Rubaiyea, Baba, Keiko, Miah, Shahjahan, Shishido, Takao, Galiano, Monica, Hashimoto, Takashi, Omoto, Shinya, Uehara, Takeki, Mifsud, Edin J., Collinson, Neil, Kuhlbusch, Klaus, Clinch, Barry, Wildum, Steffen, Barclay, Wendy S., and Hurt, Aeron C.
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INFLUENZA viruses ,INFLUENZA A virus ,RECOMBINANT viruses ,FERRET ,ANTIVIRAL agents ,INFLUENZA ,DIVERTICULITIS - Abstract
Baloxavir is approved in several countries for the treatment of uncomplicated influenza in otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected in clinical trials, but the likelihood of widespread occurrence depends on replication capacity and onward transmission. We evaluated the fitness of A/H3N2 and A/H1N1pdm09 viruses with the polymerase acidic (PA) I38T-variant conferring reduced susceptibility to baloxavir relative to wild-type (WT) viruses, using a competitive mixture ferret model, recombinant viruses and patient-derived virus isolates. The A/H3N2 PA/I38T virus showed a reduction in within-host fitness but comparable between-host fitness to the WT virus, while the A/H1N1pdm09 PA/I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although PA/I38T viruses replicate and transmit between ferrets, our data suggest that viruses with this amino acid substitution have lower fitness relative to WT and this relative fitness cost was greater in A/H1N1pdm09 viruses than in A/H3N2 viruses. Author summary: Influenza viruses are associated with considerable disease burden and circulate annually causing seasonal epidemics. Antiviral drugs can be used to treat influenza infections and help reduce the disease burden. Occasionally, treatment can lead to the emergence of viruses with reduced antiviral susceptibility. Normally such viruses have reduced 'fitness', meaning they do not tend to spread or transmit widely, however on rare occasions, oseltamivir-resistant variants have become widespread in the community, thereby reducing the utility of the drug for treatment. Baloxavir is an antiviral recently licensed in many parts of the world for the treatment of influenza. Viruses with reduced susceptibility to baloxavir have been observed in clinical trials, but the frequency of such variants in the community has remained low (<0.1% globally since 2017–2018). We evaluated the fitness of viruses in ferrets and found that although A/H1N1 and A/H3N2 viruses with reduced baloxavir susceptibility were able to replicate and transmit among ferrets, they had a moderate reduction in fitness compared to normal 'wild-type' viruses, suggesting a reduced likelihood of spread. Surveillance to monitor for the frequency of viruses with reduced baloxavir susceptibility remains important. [ABSTRACT FROM AUTHOR]
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- 2021
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19. Comprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil.
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Hashimoto, Takashi, Baba, Keiko, Inoue, Kae, Okane, Miyako, Hata, Satoshi, Shishido, Takao, Naito, Akira, Wildum, Steffen, and Omoto, Shinya
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RNA polymerases ,INFLUENZA A virus ,INFLUENZA viruses ,AMINO acids ,INFLUENZA B virus ,INFLUENZA A virus, H1N1 subtype - Abstract
Background: Baloxavir marboxil (BXM) is an approved drug that selectively targets cap‐dependent endonuclease on PA subunit in the RNA polymerase complex of influenza A and B viruses. Amino acid substitutions at position 38 in the PA subunit were identified as a major pathway for reduced susceptibility to baloxavir acid (BXA), the active form of BXM. Additionally, substitutions found at positions E23, A37, and E199 in the PA subunit impact BXA susceptibility by less than 10‐fold. Methods: We comprehensively evaluated the impact of novel amino acid substitutions identified in PA, PB1, and PB2 subunits in BXM clinical trials and influenza sequence databases by means of drug susceptibility and replicative capacity. Results: PA/I38N in A(H1N1)pdm09 and PA/I38R in A(H3N2) were newly identified as treatment‐emergent substitutions in the CAPSTONE‐2 study. The I38N substitution conferred reduced susceptibility by 24‐fold, whereas replicative capacity of the I38N‐substituted virus was impaired compared with the wild‐type. The I38R‐substituted virus was not viable in cell culture. All other mutations assessed in this extensive study did not significantly affect BXA susceptibility (< 2.4‐fold change). Conclusion: These results provide additional information on the impact of amino acid substitutions in the trimeric viral polymerase complex to BXA susceptibility and will further support influenza surveillance. [ABSTRACT FROM AUTHOR]
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- 2021
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20. Baloxavir Treatment in Adolescents With Acute Influenza: Subgroup Analysis From the CAPSTONE-1 Trial.
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Portsmouth, Simon, Hayden, Frederick G, Kawaguchi, Keiko, Ishibashi, Toru, Kinoshita, Masahiro, Shishido, Takao, Tsuchiya, Kenji, and Uehara, Takeki
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CONFIDENCE intervals ,TREATMENT duration ,TREATMENT effectiveness ,RANDOMIZED controlled trials ,PLACEBOS ,INFLUENZA ,DESCRIPTIVE statistics ,DISEASE duration ,DRUG side effects ,ACUTE diseases ,ENZYME inhibitors ,ADOLESCENCE - Abstract
Background Baloxavir marboxil has demonstrated safety and efficacy in treating adult and adolescent outpatients with acute influenza (CAPSTONE-1 trial). Here, we report a subgroup analysis of outcomes in adolescents from the trial. Methods CAPSTONE-1 was a randomized, double-blind, placebo-controlled study. Eligible adolescent outpatients (aged 12-17 years of age) were randomized in a ratio of 2:1 to a single dose of baloxavir 40/80 mg if less than/greater than or equal to 80 kg or placebo. The main outcomes were the time to alleviation of symptoms (TTAS), duration of infectious virus detection, and incidence of adverse events (AEs). Results Among 117 adolescent patients, 90 (77%) comprised the intent-to-treat infected population (63 baloxavir and 27 placebo; 88.9% A(H3N2)). The median TTAS was 38.6 hours shorter (95% confidence interval: −2.6, 68.4) in the baloxavir group compared with placebo (median TTAS, 54.1 hours vs 92.7 hours, P =.0055). The median time to sustained cessation of infectious virus detection was 72.0 hours for baloxavir compared with 120.0 hours for placebo recipients (P <.0001). Treatment-emergent PA/I38X-substituted viruses were detected in 5 of the 51 (9.8%) baloxavir recipients. In the safety population (76 baloxavir and 41 placebo), AEs were less common in baloxavir than placebo recipients (17.1% vs 34.1%; P =.0421). In the baloxavir group, no AEs except for diarrhea were reported in 2 or more patients. Conclusions Baloxavir demonstrated clinical and virologic efficacy in the otherwise healthy adolescents with acute influenza compared with placebo. There were no safety concerns identified. These results were similar to the adult population in CAPSTONE-1 and support baloxavir as a treatment option in adolescents. [ABSTRACT FROM AUTHOR]
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- 2021
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21. Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection.
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Ando, Yoshinori, Noshi, Takeshi, Sato, Kenji, Ishibashi, Toru, Yoshida, Yuki, Hasegawa, Takahiro, Onishi, Motoyasu, Kitano, Mitsutaka, Oka, Ryoko, Kawai, Makoto, Yoshida, Ryu, Sato, Akihiko, Shishido, Takao, and Naito, Akira
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VIRUS diseases ,INFLUENZA viruses ,H1N1 influenza ,PHARMACOKINETICS ,INFLUENZA B virus ,VIRUS inhibitors ,BIOLOGICAL models ,PYRIDINE ,RESEARCH ,HETEROCYCLIC compounds ,ANIMAL experimentation ,RESEARCH methodology ,ANTIVIRAL agents ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,INFLUENZA ,ESTERASES ,INFLUENZA A virus, H1N1 subtype ,MICE ,INFLUENZA A virus, H3N2 subtype - Abstract
Background: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies.Objectives: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice.Methods: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid.Results: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid.Conclusions: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings. [ABSTRACT FROM AUTHOR]- Published
- 2021
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22. The antiviral effects of baloxavir marboxil against influenza A virus infection in ferrets.
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Kitano, Mitsutaka, Matsuzaki, Takanobu, Oka, Ryoko, Baba, Kaoru, Noda, Takahiro, Yoshida, Yuki, Sato, Kenji, Kiyota, Kohei, Mizutare, Tohru, Yoshida, Ryu, Sato, Akihiko, Kamimori, Hiroshi, Shishido, Takao, and Naito, Akira
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VIRUS diseases ,INFLUENZA A virus ,FERRET ,SYMPTOMS ,TISSUE culture - Abstract
Background: Baloxavir marboxil (BXM), the oral prodrug of baloxavir acid (BXA), greatly reduces virus titers as well as influenza symptoms of uncomplicated influenza in patients. Objectives: To investigate the pharmacokinetic profiles of BXA and its efficacy against influenza A virus infection in ferrets. Methods: Ferrets were dosed orally with BXM (10 and 30 mg/kg twice daily for 1 day), oseltamivir phosphate (OSP) (5 mg/kg twice daily for 2 days) or vehicle to measure the antiviral effects of BXM and OSP. The pharmacokinetic parameters of BXA was determined after single oral dosing of BXM. Results: The maximum plasma concentrations of BXA were observed at 1.50 and 2.00 hours with the two BXM doses, which then declined with an elimination half‐life of 6.91 and 4.44 hours, respectively. BXM at both doses remained detectable in the plasma in ferrets, which may be due to higher stability in liver microsomes. BXM (10 and 30 mg/kg twice daily) treatment at Day 1 post‐infection (p.i.) reduced virus titers by ≥3 log10 of the 50% tissue culture infective doses by Day 2, which was significantly different compared with vehicle or OSP. Body temperature drops over time were significantly greater with BXM than with vehicle or OSP. Significant reduction in virus titers was also demonstrated when BXM was administrated after symptom onset at Day 2 p.i. compared with vehicle and OSP, although body temperature changes largely overlapped between Day 2 and Day 4. Conclusions: The results highlight the rapid antiviral action of BXM with post‐exposure prophylaxis or therapeutic dosing in ferrets and offer support for further research on prevention of influenza virus infection and transmission. [ABSTRACT FROM AUTHOR]
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- 2020
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23. Carryover effects of baloxavir acid in human nasopharyngeal/pharyngeal swabs on infectious titer testing of influenza virus.
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Baba, Keiko, Oka, Ryoko, Shano, Shinya, Omoto, Shinya, Noshi, Takeshi, Shishido, Takao, Naito, Akira, Kawaguchi, Keiko, Ishibashi, Toru, and Uehara, Takeki
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TITERS ,H7N9 Influenza ,PHARMACOLOGY ,ACIDS ,INFLUENZA A virus - Abstract
Baloxavir marboxil (BXM) demonstrated a rapid and profound decline in infectious viral titer 1 day after BXM administration. Rapid reduction in virus titer is a characteristic of BXM. There may be a possibility that drug carryover effects have impacts on the observed antiviral effects due to the poor correlation that was observed between viral titer reduction and alleviation of influenza symptoms. Here, we report possible carryover effects of baloxavir acid (BXA), an active form of BXM, on infectious titer testing. Our findings indicate that there is little impact of BXA carryover on the infectious titer testing. [ABSTRACT FROM AUTHOR]
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- 2020
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24. Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission.
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Lee, Leo Yi Yang, Zhou, Jie, Frise, Rebecca, Goldhill, Daniel H., Koszalka, Paulina, Mifsud, Edin J., Baba, Kaoru, Noda, Takahiro, Ando, Yoshinori, Sato, Kenji, Yuki, Aoe-Ishikawa, Shishido, Takao, Uehara, Takeki, Wildum, Steffen, Zwanziger, Elke, Collinson, Neil, Kuhlbusch, Klaus, Clinch, Barry, Hurt, Aeron C., and Barclay, Wendy S.
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PANDEMICS ,FERRET ,INFLUENZA ,SEASONAL influenza ,INFLUENZA viruses ,VIRAL transmission - Abstract
Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season and a vaccine for a novel pandemic virus manufactured using current technology will not be available fast enough to mitigate the effect of the first pandemic wave. Antivirals can be effective against many different influenza viruses but have not thus far been used extensively for outbreak control. Baloxavir, a recently licensed antiviral drug that targets the influenza virus endonuclease, has been shown to reduce virus shedding more effectively than oseltamivir, a widely used neuraminidase inhibitor drug. Thus it is possible that treatment with baloxavir might also interrupt onward virus transmission. To test this, we utilized the ferret model, which is the most commonly used animal model to study influenza virus transmission. We established a subcutaneous baloxavir administration method in ferrets which achieved similar pharmacokinetics to the approved human oral dose. Transmission studies were then conducted in two different locations with different experimental setups to compare the onward transmission of A(H1N1)pdm09 virus from infected ferrets treated with baloxavir, oseltamivir or placebo to naïve sentinel ferrets exposed either indirectly in adjacent cages or directly by co-housing. We found that baloxavir treatment reduced infectious viral shedding in the upper respiratory tract of ferrets compared to placebo, and reduced the frequency of transmission amongst sentinels in both experimental setups, even when treatment was delayed until 2 days post-infection. In contrast, oseltamivir treatment did not substantially affect viral shedding or transmission compared to placebo. We did not detect the emergence of baloxavir-resistant variants in treated animals or in untreated sentinels. Our results support the concept that antivirals which decrease viral shedding could also reduce influenza transmission in the community. Author summary: During seasonal influenza outbreaks and global pandemics, influenza can cause significant morbidity and mortality and spread rapidly. Influenza viruses constantly change, and the effectiveness of vaccination can be low if the match between the vaccine and circulating viruses is poor. However, antiviral drugs target conserved parts of the virus and therefore typically remain effective against new seasonal or pandemic strains of influenza. The new antiviral baloxavir is more effective than existing drugs, such as oseltamivir, in reducing the amount of virus particles produced by infected people, suggesting it might reduce the onward spread of influenza viruses to others. To test this, we developed an effective way to deliver baloxavir to ferrets, the best available animal model of influenza virus transmission. We then treated influenza-infected ferrets with baloxavir to determine if they were less likely to pass their virus onto healthy ferrets housed in the same cage, or in the adjacent cage. In both cases, we found that compared to oseltamivir or placebo treatment, infected ferrets treated with baloxavir produced fewer virus particles and were less likely to transmit virus to healthy ferrets. Our results suggest baloxavir can contribute to the early control of influenza outbreaks by limiting community-based viral spread. [ABSTRACT FROM AUTHOR]
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- 2020
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25. Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza.
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Uehara, Takeki, Hayden, Frederick G, Kawaguchi, Keiko, Omoto, Shinya, Hurt, Aeron C, Jong, Menno D De, Hirotsu, Nobuo, Sugaya, Norio, Lee, Nelson, Baba, Keiko, Shishido, Takao, Tsuchiya, Kenji, Portsmouth, Simon, Kida, Hiroshi, and De Jong, Menno D
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INFLUENZA viruses ,AMINO acids ,INFLUENZA ,SULFUR compounds ,PYRIDINE ,RESEARCH ,HETEROCYCLIC compounds ,VIRAL load ,RESEARCH methodology ,ANTIVIRAL agents ,EVALUATION research ,MEDICAL cooperation ,TREATMENT effectiveness ,COMPARATIVE studies ,BLIND experiment ,DRUG resistance in microorganisms ,INFLUENZA A virus, H3N2 subtype ,OSELTAMIVIR ,PHARMACODYNAMICS - Abstract
Background: Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.Methods: We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.Results: Viruses containing PA/I38X substitutions were identified 3-9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.Conclusions: The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.Clinical Trial Registration: NCT02954354. [ABSTRACT FROM AUTHOR]- Published
- 2020
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26. Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease.
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Miyagawa, Masayoshi, Akiyama, Toshiyuki, Taoda, Yoshiyuki, Takaya, Kenji, Takahashi-Kageyama, Chika, Tomita, Kenji, Yasuo, Kazuya, Hattori, Kazunari, Shano, Shinya, Yoshida, Ryu, Shishido, Takao, Yoshinaga, Tomokazu, Sato, Akihiko, and Kawai, Makoto
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- 2019
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27. Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models.
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Fukao, Keita, Ando, Yoshinori, Noshi, Takeshi, Kitano, Mitsutaka, Noda, Takahiro, Kawai, Makoto, Yoshida, Ryu, Sato, Akihiko, Shishido, Takao, and Naito, Akira
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ENDONUCLEASES ,INFLUENZA A virus ,NEURAMINIDASE ,INFLUENZA B virus ,VIRAL replication ,VIRUS diseases ,THERAPEUTICS - Abstract
Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log
10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status. [ABSTRACT FROM AUTHOR]- Published
- 2019
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28. Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection.
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Fukao, Keita, Noshi, Takeshi, Yamamoto, Atsuko, Kitano, Mitsutaka, Ando, Yoshinori, Noda, Takahiro, Baba, Kaoru, Matsumoto, Kazumi, Higuchi, Naoko, Ikeda, Minoru, Shishido, Takao, and Naito, Akira
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ENDONUCLEASES ,INFLUENZA ,NEURAMINIDASE ,ORTHOMYXOVIRUSES ,OSELTAMIVIR ,ANIMAL experimentation ,ANTIVIRAL agents ,BIOLOGICAL models ,COMBINATION drug therapy ,COMPARATIVE studies ,DRUG synergism ,HETEROCYCLIC compounds ,RESEARCH methodology ,MEDICAL cooperation ,MICE ,ORAL drug administration ,PYRIDINE ,RESEARCH ,SULFUR compounds ,SURVIVAL analysis (Biometry) ,EVALUATION research ,INFLUENZA A virus ,TREATMENT effectiveness ,ORTHOMYXOVIRUS infections - Abstract
Objectives: Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for the treatment of influenza virus infection. We evaluated the efficacy of delayed oral treatment with baloxavir marboxil in combination with a neuraminidase inhibitor in a mouse model of lethal influenza virus infection.Methods: The inhibitory potency of baloxavir acid (the active form of baloxavir marboxil) in combination with neuraminidase inhibitors was tested in vitro. The therapeutic effects of baloxavir marboxil and oseltamivir phosphate, or combinations thereof, were evaluated in mice lethally infected with influenza virus A/PR/8/34; treatments started 96 h post-infection.Results: Combinations of baloxavir acid and neuraminidase inhibitor exhibited synergistic potency against viral replication by means of inhibition of cytopathic effects in vitro. In mice, baloxavir marboxil monotherapy (15 or 50 mg/kg twice daily) significantly and dose-dependently reduced virus titre 24 h after administration and completely prevented mortality, whereas oseltamivir phosphate treatments were not as effective. In this model, a suboptimal dose of baloxavir marboxil (0.5 mg/kg twice daily) in combination with oseltamivir phosphate provided additional efficacy compared with monotherapy in terms of virus-induced mortality, elevation of cytokine/chemokine levels and pathological changes in the lung.Conclusions: Baloxavir marboxil monotherapy with 96 h-delayed oral dosing achieved drastic reductions in virus titre, inflammatory response and mortality in a mouse model. Combination treatment with baloxavir acid and oseltamivir acid in vitro and baloxavir marboxil and oseltamivir phosphate in mice produced synergistic responses against influenza virus infections, suggesting that treating humans with the combination may be beneficial. [ABSTRACT FROM AUTHOR]- Published
- 2019
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29. Clinical and virologic effects of four neuraminidase inhibitors in influenza A virus-infected children (aged 4-12 years): an open-label, randomized study in Japan.
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Hirotsu, Nobuo, Saisho, Yutaka, Hasegawa, Takahiro, and Shishido, Takao
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HYDROCARBONS ,ANTIVIRAL agents ,ORGANIC compounds ,OSELTAMIVIR ,COMPARATIVE studies ,GLYCOSIDASES ,INFLUENZA ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,TIME ,EVALUATION research ,INFLUENZA A virus ,RANDOMIZED controlled trials ,TREATMENT effectiveness ,ACYCLIC acids ,CHEMICAL inhibitors ,THERAPEUTICS - Abstract
Background: Neuraminidase inhibitors (NAIs) reduce influenza symptoms but clear evidence of relationships between viral titer reduction and symptom alleviation is lacking. This open-label, randomized study evaluated differences in viral dynamics between NAIs, and relationships between viral dynamics and influenza symptoms (trial registration number: UMIN000012670).Methods: Patients (n = 123) aged 4-12 years with influenza A virus infection were randomized to intravenous peramivir, oral oseltamivir, inhaled zanamivir, or inhaled laninamivir. Patients received regular viral assessments of nasal discharge, at least until rapid antigen tests were negative. Time to virus clearance, based on influenza virus titer, was the primary endpoint.Results: Peramivir recipients had a significantly shorter time to virus clearance than oseltamivir recipients (adjusted p = 0.035). Comparisons between the peramivir group and other NAI groups were not significant. There were no significant inter-group differences in other clinical efficacy endpoints (time to resolution of fever, time to alleviation of symptoms). However, the peramivir group showed a smaller numerical proportion of relapses with fever or positive virus than the other groups.Conclusions: The time to virus clearance was significantly shorter with peramivir than with oseltamivir. Although no clear relationship between virus dynamics and symptoms was observed, ongoing studies should clarify the situation. [ABSTRACT FROM AUTHOR]- Published
- 2018
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30. Characterization of the In Vitro and In Vivo Efficacy of Baloxavir Marboxil against H5 Highly Pathogenic Avian Influenza Virus Infection.
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Taniguchi, Keiichi, Ando, Yoshinori, Kobayashi, Masanori, Toba, Shinsuke, Nobori, Haruaki, Sanaki, Takao, Noshi, Takeshi, Kawai, Makoto, Yoshida, Ryu, Sato, Akihiko, Shishido, Takao, Naito, Akira, Matsuno, Keita, Okamatsu, Masatoshi, Sakoda, Yoshihiro, and Kida, Hiroshi
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AVIAN influenza A virus ,VIRUS diseases ,AVIAN influenza ,H5N1 Influenza ,INFLUENZA A virus ,INFLUENZA viruses - Abstract
Human infections caused by the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threaten public health. The susceptibility of HPAIVs to baloxavir acid (BXA), a new class of inhibitors for the influenza virus cap-dependent endonuclease, has been confirmed in vitro, but it has not yet been fully characterized. Here, the efficacy of BXA against HPAIVs, including recent H5N8 variants, was assessed in vitro. The antiviral efficacy of baloxavir marboxil (BXM) in H5N1 virus-infected mice was also investigated. BXA exhibited similar in vitro activities against H5N1, H5N6, and H5N8 variants tested in comparison with seasonal and other zoonotic strains. Compared with oseltamivir phosphate (OSP), BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate, the A/Hong Kong/483/1997 strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, thereby preventing acute lung inflammation and reducing mortality. Furthermore, compared with BXM or OSP monotherapy, combination treatments with BXM and OSP using a 48-h delayed treatment model showed a more potent effect on viral replication in the organs, accompanied by improved survival. In conclusion, BXM has a potent antiviral efficacy against H5 HPAIV infections. [ABSTRACT FROM AUTHOR]
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- 2022
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31. Transformation of BALB3T3 cells caused by over-expression of rat CD98 heavy chain (HC) requires its association with light chain: Mis-sense mutation in a cysteine residue of CD98HC eliminates its transforming activity.
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Shishido, Takao, Uno, Shinsuke, Kamohara, Masazumi, Tsuneoka-Suzuki, Takako, Hashimoto, Yoshiyuki, Enomoto, Takemi, and Masuko, Takashi
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- 2000
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32. Colocalization of GP125/CD98 with Tropomyosin Isoforms at the Cell-Cell Adhesion Boundary1.
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Shishido, Takao, Ohkawa, Mayumi, Itoh, Akihiro, Enomoto, Takemi, Hashimoto, Yoshiyuki, and Masuko, Takashi
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- 2000
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33. HISTAMINE IMMUNOCYTOCHEMISTRY ON ROUTINE PARAFFIN-EMBEDDED SECTIONS IN THE RAT STOMACH.
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Shishido, Takao and Matsuzawa, Toshiaki
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HISTAMINE , *IMMUNOCYTOCHEMISTRY - Abstract
A technique has been adapted from methods that maintain the same staining quality as that produced by perfusion fixation and immunocytochemistry on frozen sections of the stomach, and that can be easily incorporated into the routine procedures for paraffin embedded sections in toxicity studies in the rat. The technique is as follows: The rat is killed by exsanguination under ether anesthesia and the stomach is pinned on a corkboard. The stomach is then immediately immersed in 4% 1-ethyl-3(3-dimethyle aminoprophyl)carbodiimide in 0.1 M phosphate-buffered solution, pH 7.4, at 4 C for 2 h and then in 4% paraformaldehyde in the same buffer solution for 2 h. The tissue is irradiated by microwaves twice at 250 W for 20 s each time. The tissue is then embedded in paraffin wax at 58 to 60 C. This technique has proved suitable for staining histamine-containing cells in the stomach and can be incorporated as part of the routine necropsy on routine large toxicity studies. The process has improved both the identification of histamine-containing cells and the storage quality of the fixed tissue. Microwave irradiation and storage of the sample at 4 C in 80% EtOH for 12 weeks did not affect the staining affinity. These methods have reduced the workload by 30 to40%compared to the procedureof perfusion fixation and frozen section. [ABSTRACT FROM AUTHOR]
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- 1998
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34. Baloxavir marboxil in Japanese patients with seasonal influenza: Dose response and virus type/subtype outcomes from a randomized phase 2 study.
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Watanabe, Akira, Ishida, Tadashi, Hirotsu, Nobuo, Kawaguchi, Keiko, Ishibashi, Toru, Shishido, Takao, Sato, Chisako, Portsmouth, Simon, Tsuchiya, Kenji, and Uehara, Takeki
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ANTIVIRAL agents , *SEASONAL influenza , *INFLUENZA treatment , *DRUG dosage , *RANDOMIZED controlled trials - Abstract
Abstract Background Baloxavir marboxil (baloxavir) is an antiviral drug that inhibits the viral "cap-snatching" step in virus RNA transcription initiation. In Phase 2 study, baloxavir significantly shortend the time to alleviation of symptoms (TTAS) and showed significantly greater reduction in influenza virus titer compared with placebo. This provides additional outcomes including efficacy against virus types/subtypes and pharmacokinetic/pharmacodynamic (PK/PD) analysis. Methods Subgroup analyses by virus types/subtype were conducted for the primary and key secondary endpoints. Blood samples were collected totally at 2 to 5 points including Day 2 after baloxavir dosing. PK/PD analyses were conducted for TTAS and change in virus titer using the liner model and the E max model, respectively. Results The median TTAS in each baloxavir dose group was significantly shorter than in the placebo group for patients with A/H1N1pdm virus, and was numerically shorter than the placebo group for patients with A/H3N2 and type B virus. Baloxavir significantly reduced virus titer within 1 day after treatment: for A/H1N1pdm, A/H3N2, and B virus, all 3 doses of baloxavir marboxil reduced virus titer on Day 2 to a greater extent than placebo. No clear PK/PD relationships were found for the TTAS, but the larger reduction in virus titer was observed in increasing C 24. Conclusion These results support that baloxavir marboxil will be effective against a range of virus types/subtypes. Highlights • Baloxavir marboxil is an antiviral drug that inhibits influenza virus RNA transcription initiation. • Baloxavir marboxil is clinically and virologically effective against seasonal influenza infection in Japanese adults. • A dose as low as 10 mg of baloxavir marboxil reduced time to alleviation of symptoms and virus titer compared with placebo. • Baloxavir marboxil was effective regardless of virus types/subtypes (A/H1N1pdm, A/H3N2, and B). [ABSTRACT FROM AUTHOR]
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- 2019
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35. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit.
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Noshi, Takeshi, Kitano, Mitsutaka, Taniguchi, Keiichi, Yamamoto, Atsuko, Omoto, Shinya, Baba, Keiko, Hashimoto, Takashi, Ishida, Kayo, Kushima, Yukihiro, Hattori, Kazunari, Kawai, Makoto, Yoshida, Ryu, Kobayashi, Masanori, Yoshinaga, Tomokazu, Sato, Akihiko, Okamatsu, Masatoshi, Sakoda, Yoshihiro, Kida, Hiroshi, Shishido, Takao, and Naito, Akira
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ENDONUCLEASES , *ENZYME inhibitors , *INFLUENZA viruses , *POLYMERASES , *GENETIC transcription - Abstract
Abstract Cap-dependent endonuclease (CEN) resides in the PA subunit of the influenza virus and mediates the critical "cap-snatching" step of viral RNA transcription, which is considered to be a promising anti-influenza target. Here, we describe in vitro characterization of a novel CEN inhibitor, baloxavir acid (BXA), the active form of baloxavir marboxil (BXM). BXA inhibits viral RNA transcription via selective inhibition of CEN activity in enzymatic assays, and inhibits viral replication in infected cells without cytotoxicity in cytopathic effect assays. The antiviral activity of BXA is also confirmed in yield reduction assays with seasonal type A and B viruses, including neuraminidase inhibitor-resistant strains. Furthermore, BXA shows broad potency against various subtypes of influenza A viruses (H1N2, H5N1, H5N2, H5N6, H7N9 and H9N2). Additionally, serial passages of the viruses in the presence of BXA result in isolation of PA/I38T variants with reduced BXA susceptibility. Phenotypic and genotypic analyses with reverse genetics demonstrate the mechanism of BXA action via CEN inhibition in infected cells. These results reveal the in vitro characteristics of BXA and support clinical use of BXM to treat influenza. Highlights • In vitro characterization of a CEN inhibitor baloxavir acid (BXA), the active form of baloxavir marboxil, was conducted. • BXA selectively blocks CEN activity of the viral polymerase complex in enzymatic assay. • BXA exhibits potent and broad activities against various types of influenza viruses. • In vitro drug resistant isolation study supports BXA targets CEN of PA subunit. [ABSTRACT FROM AUTHOR]
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- 2018
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36. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents.
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Baloxavir Marboxil Investigators Group, Hayden, Frederick G., Kota Yamada, Portsmouth, Simon, Keiko Kawaguchi, Takao Shishido, Masatsugu Arai, Kenji Tsuchiya, Takeki Uehara, Akira Watanabe, Sugaya, Norio, Hirotsu, Nobuo, Ishida, Tadashi, Sekino, Hisakuni, Yamada, Kota, Kawaguchi, Keiko, Shishido, Takao, Arai, Masatsugu, Tsuchiya, Kenji, and Uehara, Takeki
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OSELTAMIVIR , *ANTIVIRAL agents , *CLINICAL trials , *COMPARATIVE studies , *ESTERASES , *INFLUENZA , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *STATISTICAL sampling , *VIRAL load , *EVALUATION research , *RANDOMIZED controlled trials , *BLIND experiment , *KAPLAN-Meier estimator , *CHEMICAL inhibitors , *THERAPEUTICS - Abstract
Background: Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.Methods: We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.Results: In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.Conclusions: Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .). [ABSTRACT FROM AUTHOR]- Published
- 2018
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37. Discovery of novel 5-hydroxy-4-pyridone-3-carboxy acids as potent inhibitors of influenza Cap-dependent endonuclease.
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Miyagawa, Masayoshi, Akiyama, Toshiyuki, Mikamiyama-Iwata, Minako, Hattori, Kazunari, Kurihara, Naoko, Taoda, Yoshiyuki, Takahashi-Kageyama, Chika, Kurose, Noriyuki, Mikamiyama, Hidenori, Suzuki, Naoyuki, Takaya, Kenji, Tomita, Kenji, Matsuo, Kenji, Morimoto, Kenji, Yoshida, Ryu, Shishido, Takao, Yoshinaga, Tomokazu, Sato, Akihiko, and Kawai, Makoto
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DRUG development , *INHIBITORY Concentration 50 , *ENDONUCLEASES , *NIACIN , *CHELATES , *THERAPEUTICS - Abstract
We report the discovery of a novel series of influenza Cap-dependent EndoNuclease (CEN) inhibitors based on the 4-pyridone-carboxylic acid (PYXA) scaffold, which were found from our chelate library. Our SAR research revealed the lipophilic domain to be the key to CEN inhibition. In particular, the position between the chelate and the lipophilic domain in the derivatives was essential for enhancing the potency. Our study, based on virtual modeling, led to the identification of 2y as a potent CEN inhibitor with an IC 50 of 5.12 nM. [ABSTRACT FROM AUTHOR]
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- 2016
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38. Kinase Control of Latent HIV-1 Infection: PIM-1 Kinase as a Major Contributor to HIV-1 Reactivation.
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Duverger, Alexandra, Wolschendorf, Frank, Anderson, Joshua C., Wagner, Frederic, Bosque, Alberto, Shishido, Takao, Jones, Jennifer, Planelles, Vicente, Willey, Christopher, Cron, Randall Q., and Kutsch, Olaf
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HIV infections , *THERAPEUTICS , *KINASES , *T cells , *CD4 antigen , *HOST-virus relationships - Abstract
Despite the clinical relevance of latent HIV-1 infection as a block to HIV-1 eradication, the molecular biology of HIV-1 latency remains incompletely understood. We recently demonstrated the presence of a gatekeeper kinase function that controls latent HIV-1 infection. Using kinase array analysis, we here expand on this finding and demonstrate that the kinase activity profile of latently HIV-1-infected T cells is altered relative to that of uninfected T cells. A ranking of altered kinases generated from these kinome profile data predicted PIM-1 kinase as a key switch involved in HIV-1 latency control. Using genetic and pharmacologic perturbation strategies, we demonstrate that PIM-1 activity is indeed required for HIV-1 reactivation in T cell lines and primary CD4 T cells. The presented results thus confirm that kinases are key contributors to HIV-1 latency control. In addition, through mutational studies we link the inhibitory effect of PIM-1 inhibitor IV (PIMi IV) on HIV-1 reactivation to an AP-1 motif in the CD28-responsive element of the HIV-1 long terminal repeat (LTR). The results expand our conceptual understanding of the dynamic interactions of the host cell and the latent HIV-1 integration event and position kinome profiling as a research tool to reveal novel molecular mechanisms that can eventually be targeted to therapeutically trigger HIV-1 reactivation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
39. Identification of quinolone derivatives as effective anti-Dengue virus agents.
- Author
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Nobori, Haruaki, Uemura, Kentaro, Toba, Shinsuke, Sanaki, Takao, Shishido, Takao, Hall, William W., Orba, Yasuko, Sawa, Hirofumi, and Sato, Akihiko
- Subjects
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VIRAL replication , *TROPICAL medicine , *DENGUE viruses , *COMMUNICABLE diseases , *SMALL molecules - Abstract
Dengue virus (DENV) infection is one of the most important infectious diseases in tropical and subtropical regions around the world. Previously, we performed an initial phenotypic screening of 7000 compounds using DENV type 2 (DENV2)-infected BHK-21 cells to identify small molecules which could inhibit virus replication. In this study, we describe two novel compounds with anti-DENV2 activity, tentatively named Compound-X and Compound-Y. Both compounds possess a quinolone skeleton, and the EC 50 s of Compound-X and Compound-Y against DENV2 were 3.9 μM and 9.2 μM, respectively. Based on a DENV replicon assay, it was suggested that these compounds have anti-DENV2 activity by inhibition of a step in virus replication. Furthermore, using mutational analysis we obtained compounds-resistant to DENV2 infection and identified a mutation, V130A in the NS5 methyltransferase (MTase) domain. However, these compounds did not inhibit MTase activity. In addition, incorporation of an additional NS1 N246D mutation with the NS5 V130A mutation in DENV2 resulted in recovery of viral replication and a further reduction of the sensitivity to the quinolone compounds by an unknown mechanism. Therefore further investigations are required to clarify the antiviral mechanisms of these quinolone compounds. • Quinolone-containing Compound-X and Compound-Y have anti- DENV activity. • The DENV2 NS5 V130A mutant exhibited some resistance to Compound-X and Compound-Y. • The NS1 N246D/NS5 V130A DENV2 double mutant restored viral replication and was also resistant to Compound-X and Compound-Y. • Compound-X and Compound-Y were found not to inhibit methyltransferase (MTase) activity. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
40. Dihydrodibenzothiepine: Promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitor.
- Author
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Taoda, Yoshiyuki, Miyagawa, Masayoshi, Akiyama, Toshiyuki, Tomita, Kenji, Hasegawa, Yasushi, Yoshida, Ryu, Noshi, Takeshi, Shishido, Takao, and Kawai, Makoto
- Subjects
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STRUCTURE-activity relationships , *INFLUENZA - Abstract
This work describes a set of discovery research studies of an influenza cap-dependent endonuclease (CEN) inhibitor with a carbamoyl pyridone bicycle (CAB) scaffold. Using influenza CEN inhibitory activity, antiviral activity and pharmacokinetic (PK) parameters as indices, structure activity relationships (SAR) studies were performed at the N-1 and N-3 positions on the CAB scaffold, which is a unique template to bind two metals. The hydrophobic substituent at the N-1 position is extremely important for CEN inhibitory activity and antiviral activity, and dihydrodibenzothiepine is the most promising pharmacophore. The compound (S)-13i showed potent virus titer reduction over oseltamivir phosphate in an in vivo mouse model. The CAB compound described herein served as the lead compound of baloxavir marboxil with a tricyclic scaffold, which was approved in Japan and the USA in 2018. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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