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Akihiko Sato
Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd, Osaka, Japan

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Short Biography

Hokkaido University Research Center for Zoonosis Control Nishi, 10-chome, Kita 20-jo, Kitaku, Sapporo, Hokkaido 001-0020, Japan

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Journal article
Published: 08 March 2021 in Scientific Reports
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Although the spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a worldwide pandemic, there are currently no virus-specific drugs that are fully effective against SARS-CoV-2. Only a limited number of human-derived cells are capable of supporting SARS-CoV-2 replication and the infectivity of SARS-CoV-2 in these cells remains poor. In contrast, monkey-derived Vero cells are highly susceptibility to infection with SARS-CoV-2, although they are not suitable for the study of antiviral effects by small molecules due to their limited capacity to metabolize drugs compared to human-derived cells. In this study, our goal was to generate a virus-susceptible human cell line that would be useful for the identification and testing of candidate drugs. Towards this end, we stably transfected human lung-derived MRC5 cells with a lentiviral vector encoding angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2. Our results revealed that SARS-CoV-2 replicates efficiently in MRC5/ACE2 cells. Furthermore, viral RNA replication and progeny virus production were significantly reduced in response to administration of the replication inhibitor, remdesivir, in MRC5/ACE2 cells compared with Vero cells. We conclude that the MRC5/ACE2 cells will be important in developing specific anti-viral therapeutics and will assist in vaccine development to combat SARS-CoV-2 infections.

ACS Style

Kentaro Uemura; Michihito Sasaki; Takao Sanaki; Shinsuke Toba; Yoshimasa Takahashi; Yasuko Orba; William W. Hall; Katsumi Maenaka; Hirofumi Sawa; Akihiko Sato. MRC5 cells engineered to express ACE2 serve as a model system for the discovery of antivirals targeting SARS-CoV-2. Scientific Reports 2021, 11, 1 -9.

AMA Style

Kentaro Uemura, Michihito Sasaki, Takao Sanaki, Shinsuke Toba, Yoshimasa Takahashi, Yasuko Orba, William W. Hall, Katsumi Maenaka, Hirofumi Sawa, Akihiko Sato. MRC5 cells engineered to express ACE2 serve as a model system for the discovery of antivirals targeting SARS-CoV-2. Scientific Reports. 2021; 11 (1):1-9.

Chicago/Turabian Style

Kentaro Uemura; Michihito Sasaki; Takao Sanaki; Shinsuke Toba; Yoshimasa Takahashi; Yasuko Orba; William W. Hall; Katsumi Maenaka; Hirofumi Sawa; Akihiko Sato. 2021. "MRC5 cells engineered to express ACE2 serve as a model system for the discovery of antivirals targeting SARS-CoV-2." Scientific Reports 11, no. 1: 1-9.

Communication
Published: 28 February 2021 in Viruses
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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry. Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated. Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2. In addition, SARS-CoV-1 and SARS-CoV-2 share the same TTSPs in the viral entry process. Our study demonstrates the impact of host TTSPs on infection of SARS-CoV-2, which may have implications for cell and tissue tropism, for pathogenicity, and potentially for vaccine development.

ACS Style

Mai Kishimoto; Kentaro Uemura; Takao Sanaki; Akihiko Sato; William Hall; Hiroaki Kariwa; Yasuko Orba; Hirofumi Sawa; Michihito Sasaki. TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein. Viruses 2021, 13, 384 .

AMA Style

Mai Kishimoto, Kentaro Uemura, Takao Sanaki, Akihiko Sato, William Hall, Hiroaki Kariwa, Yasuko Orba, Hirofumi Sawa, Michihito Sasaki. TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein. Viruses. 2021; 13 (3):384.

Chicago/Turabian Style

Mai Kishimoto; Kentaro Uemura; Takao Sanaki; Akihiko Sato; William Hall; Hiroaki Kariwa; Yasuko Orba; Hirofumi Sawa; Michihito Sasaki. 2021. "TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein." Viruses 13, no. 3: 384.

Journal article
Published: 04 November 2020 in Antiviral Research
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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 EC50s 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.

ACS Style

Haruaki Nobori; Kentaro Uemura; Shinsuke Toba; Takao Sanaki; Takao Shishido; William W. Hall; Yasuko Orba; Hirofumi Sawa; Akihiko Sato. Identification of quinolone derivatives as effective anti-Dengue virus agents. Antiviral Research 2020, 184, 104969 .

AMA Style

Haruaki Nobori, Kentaro Uemura, Shinsuke Toba, Takao Sanaki, Takao Shishido, William W. Hall, Yasuko Orba, Hirofumi Sawa, Akihiko Sato. Identification of quinolone derivatives as effective anti-Dengue virus agents. Antiviral Research. 2020; 184 ():104969.

Chicago/Turabian Style

Haruaki Nobori; Kentaro Uemura; Shinsuke Toba; Takao Sanaki; Takao Shishido; William W. Hall; Yasuko Orba; Hirofumi Sawa; Akihiko Sato. 2020. "Identification of quinolone derivatives as effective anti-Dengue virus agents." Antiviral Research 184, no. : 104969.

Research
Published: 01 December 2019 in The FASEB Journal
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Dengue fever is an acute febrile infectious disease caused by dengue virus (DENV). Despite the significant public health concerns posed by DENV, there are currently no effective anti-DENV therapeutic agents. To develop such drugs, a better understanding of the detailed mechanisms of DENV infection is needed. Both lipid metabolism and lipid synthesis are activated in DENV-infected cells, so we used lipid screening to identify potential antiviral lipid molecules. We identified 1-stearoyl-2-arachidonoyl-phosphatidylinositol (SAPI), which is the most abundant endogenous phosphatidylinositol (PI) molecular species, as an anti-DENV lipid molecule. SAPI suppressed the cytopathic effects induced by DENV2 infection as well as the replication of all DENV serotypes without inhibiting the entry of DENV2 into host cells. However, no other PI molecular species or PI metabolites, including lysophosphatidylinositols and phosphoinositides, displayed anti-DENV2 activity. Furthermore, SAPI suppressed the production of DENV2 infection-induced cytokines and chemokines, including C-C motif chemokine ligand (CCL)5, CCL20, C-X-C chemokine ligand 8, IL-6, and IFN-β. SAPI also suppressed the TNF-α production induced by LPS stimulation in macrophage cells differentiated from THP-1 cells. Our results demonstrated that SAPI is an endogenous inhibitor of DENV and modulated inflammatory responses in DENV2-infected cells, at least in part via TLR 4.—Sanaki, T., Wakabayashi, M., Yoshioka, T., Yoshida, R., Shishido, T., Hall, W. W., Sawa, H., Sato, A. Inhibition of dengue virus infection by 1-stearoyl-2-arachidonoyl-phosphatidylinositol in vitro. FASEB J. 33, 13866-13881 (2019). www.fasebj.org

ACS Style

Takao Sanaki; Masato Wakabayashi; Takeshi Yoshioka; Ryu Yoshida; Takao Shishido; William W. Hall; Hirofumi Sawa; Akihiko Sato. Inhibition of dengue virus infection by 1-stearoyl-2-arachidonoyl-phosphatidylinositolin vitro. The FASEB Journal 2019, 33, 13866 -13881.

AMA Style

Takao Sanaki, Masato Wakabayashi, Takeshi Yoshioka, Ryu Yoshida, Takao Shishido, William W. Hall, Hirofumi Sawa, Akihiko Sato. Inhibition of dengue virus infection by 1-stearoyl-2-arachidonoyl-phosphatidylinositolin vitro. The FASEB Journal. 2019; 33 (12):13866-13881.

Chicago/Turabian Style

Takao Sanaki; Masato Wakabayashi; Takeshi Yoshioka; Ryu Yoshida; Takao Shishido; William W. Hall; Hirofumi Sawa; Akihiko Sato. 2019. "Inhibition of dengue virus infection by 1-stearoyl-2-arachidonoyl-phosphatidylinositolin vitro." The FASEB Journal 33, no. 12: 13866-13881.

Journal article
Published: 30 November 2018 in Japanese Journal of Infectious Diseases
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Dengue virus (DENV) has a considerable impact on global health and causes morbidity and mortality each year. Through the passages of a DENV2 in BHK-21 cells, we have isolated a mutant clone of DENV2 which reveals cytopathic effects (CPE) rapidly compared to the parent strain in BHK-21 cells. To investigate the relationship between amino acid mutations and proliferation activity of the isolated DENV2 clone, we performed full genome sequencing and identified three amino acid mutations in its coding region, the Envelope (Env) T120K, NS4A M85T and NS4B G124A, compared to that of the parent strain. Genetically-modified recombinant DENV2 (rDENV2) carrying the NS4A M85T and NS4B G124A mutations produced higher titers of progeny virus in BHK-21, Vero and Huh-7 cells compared to wild-type (WT) rDENV2. Surprisingly, rDENV2 with mutations at NS4A M85T and NS4B G124A did not produce any plaques in C6/36 mosquito cell lines. Furthermore, rDENV2 possessing only the NS4B G124A mutation did not produce any plaques in C6/36 cells; however, it had higher viral titers in Vero and Huh-7 cells compared to WT rDENV2. Our results clearly showed that the DENV2 NS4B G124A mutation has opposing effects on viral proliferation in certain mammalian cells and mosquito cells.

ACS Style

Jumpei Fujiki; Haruaki Nobori; Akihiko Sato; Michihito Sasaki; Michael Carr; William Walmsley Hall; Yasuko Orba; Hirofumi Sawa. Single Amino Acid Mutation in Dengue Virus NS4B Protein Has Opposing Effects on Viral Proliferation in Mammalian and Mosquito Cells. Japanese Journal of Infectious Diseases 2018, 71, 448 -454.

AMA Style

Jumpei Fujiki, Haruaki Nobori, Akihiko Sato, Michihito Sasaki, Michael Carr, William Walmsley Hall, Yasuko Orba, Hirofumi Sawa. Single Amino Acid Mutation in Dengue Virus NS4B Protein Has Opposing Effects on Viral Proliferation in Mammalian and Mosquito Cells. Japanese Journal of Infectious Diseases. 2018; 71 (6):448-454.

Chicago/Turabian Style

Jumpei Fujiki; Haruaki Nobori; Akihiko Sato; Michihito Sasaki; Michael Carr; William Walmsley Hall; Yasuko Orba; Hirofumi Sawa. 2018. "Single Amino Acid Mutation in Dengue Virus NS4B Protein Has Opposing Effects on Viral Proliferation in Mammalian and Mosquito Cells." Japanese Journal of Infectious Diseases 71, no. 6: 448-454.

Journal article
Published: 11 October 2018 in Antiviral Research
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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.

ACS Style

Takeshi Noshi; Mitsutaka Kitano; Keiichi Taniguchi; Atsuko Yamamoto; Shinya Omoto; Keiko Baba; Takashi Hashimoto; Kayo Ishida; Yukihiro Kushima; Kazunari Hattori; Makoto Kawai; Ryu Yoshida; Masanori Kobayashi; Tomokazu Yoshinaga; Akihiko Sato; Masatoshi Okamatsu; Yoshihiro Sakoda; Hiroshi Kida; Takao Shishido; Akira Naito. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Research 2018, 160, 109 -117.

AMA Style

Takeshi Noshi, Mitsutaka Kitano, Keiichi Taniguchi, Atsuko Yamamoto, Shinya Omoto, Keiko Baba, Takashi Hashimoto, Kayo Ishida, Yukihiro Kushima, Kazunari Hattori, Makoto Kawai, Ryu Yoshida, Masanori Kobayashi, Tomokazu Yoshinaga, Akihiko Sato, Masatoshi Okamatsu, Yoshihiro Sakoda, Hiroshi Kida, Takao Shishido, Akira Naito. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Research. 2018; 160 ():109-117.

Chicago/Turabian Style

Takeshi Noshi; Mitsutaka Kitano; Keiichi Taniguchi; Atsuko Yamamoto; Shinya Omoto; Keiko Baba; Takashi Hashimoto; Kayo Ishida; Yukihiro Kushima; Kazunari Hattori; Makoto Kawai; Ryu Yoshida; Masanori Kobayashi; Tomokazu Yoshinaga; Akihiko Sato; Masatoshi Okamatsu; Yoshihiro Sakoda; Hiroshi Kida; Takao Shishido; Akira Naito. 2018. "In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit." Antiviral Research 160, no. : 109-117.

Journal article
Published: 01 July 2018 in Antiviral Research
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Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic fever/dengue shock syndrome. At present, no antiviral drugs are available for treatment DENV infections. In this study, a screening system based on a DENV-infected cell-based assay identified a novel anti-DENV agent with a benzimidazole skeleton, named Compound-B, which demonstrated antiviral activity specific to four DENV serotypes (EC50: 1.32-4.12 μM). Analysis of a single amino acid substitution of Compound-B-resistant DENV2 revealed that mutation C87S in the non-structural protein 4A (NS4A) contributes to resistance to Compound-B.

ACS Style

Haruaki Nobori; Shinsuke Toba; Ryu Yoshida; William W. Hall; Yasuko Orba; Hirofumi Sawa; Akihiko Sato. Identification of Compound-B, a novel anti-dengue virus agent targeting the non-structural protein 4A. Antiviral Research 2018, 155, 60 -66.

AMA Style

Haruaki Nobori, Shinsuke Toba, Ryu Yoshida, William W. Hall, Yasuko Orba, Hirofumi Sawa, Akihiko Sato. Identification of Compound-B, a novel anti-dengue virus agent targeting the non-structural protein 4A. Antiviral Research. 2018; 155 ():60-66.

Chicago/Turabian Style

Haruaki Nobori; Shinsuke Toba; Ryu Yoshida; William W. Hall; Yasuko Orba; Hirofumi Sawa; Akihiko Sato. 2018. "Identification of Compound-B, a novel anti-dengue virus agent targeting the non-structural protein 4A." Antiviral Research 155, no. : 60-66.

Journal article
Published: 01 April 2018 in Antiviral Research
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Cabotegravir (CAB, S/GSK1265744) is an investigational second-generation integrase strand transfer inhibitor (INSTI) with a chemical structure similar to dolutegravir. CAB is under development as a long-acting injectable formulation for treatment of HIV-1 infection and for pre-exposure prophylaxis. We conducted an in vitro passage study of raltegravir- or elvitegravir-resistant signature mutants in the presence of CAB to characterize the resistance profile of this drug. During passage with Q148H virus, G140S arose by day 14, followed by G149A and C56S. Using site-directed mutagenesis, we obtained HIV molecular clones containing mutations encoding C56S and G149A in the integrase-coding region. Those substitutions were characterized in vitro as INSTI-resistance-associated secondary resistance mutations. Signature mutant viruses G140S/Q148H in which C56S and G149A were added acquired further INSTI resistance in conjunction with diminished integration activity, which yielded slower growth under drug-free conditions.

ACS Style

Tomokazu Yoshinaga; Takahiro Seki; Shigeru Miki; Tadashi Miyamoto; Akemi Suyama-Kagitani; Shinobu Kawauchi-Miki; Masanori Kobayashi; Akihiko Sato; Eugene Stewart; Mark Underwood; Tamio Fujiwara. Novel secondary mutations C56S and G149A confer resistance to HIV-1 integrase strand transfer inhibitors. Antiviral Research 2018, 152, 1 -9.

AMA Style

Tomokazu Yoshinaga, Takahiro Seki, Shigeru Miki, Tadashi Miyamoto, Akemi Suyama-Kagitani, Shinobu Kawauchi-Miki, Masanori Kobayashi, Akihiko Sato, Eugene Stewart, Mark Underwood, Tamio Fujiwara. Novel secondary mutations C56S and G149A confer resistance to HIV-1 integrase strand transfer inhibitors. Antiviral Research. 2018; 152 ():1-9.

Chicago/Turabian Style

Tomokazu Yoshinaga; Takahiro Seki; Shigeru Miki; Tadashi Miyamoto; Akemi Suyama-Kagitani; Shinobu Kawauchi-Miki; Masanori Kobayashi; Akihiko Sato; Eugene Stewart; Mark Underwood; Tamio Fujiwara. 2018. "Novel secondary mutations C56S and G149A confer resistance to HIV-1 integrase strand transfer inhibitors." Antiviral Research 152, no. : 1-9.

Journal article
Published: 01 August 2017 in Bioorganic & Medicinal Chemistry Letters
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NS2B-NS3 protease is an essential enzyme for the replication of dengue virus (DENV), which continues to be a serious threat to worldwide public health. We designed and synthesized a series of cyclic peptides mimicking the substrates of this enzyme, and assayed their activity against the DENV-2 NS2B-NS3 protease. The introduction of aromatic residues at the appropriate positions and conformational restriction generated the most promising cyclic peptide with an IC50 of 0.95μM against NS2B-NS3 protease. Cyclic peptides with proper positioning of additional arginines and aromatic residues exhibited antiviral activity against DENV. Furthermore, replacing the C-terminal amide bond of the polybasic amino acid sequence with an amino methylene moiety stabilized the cyclic peptides against hydrolysis by NS2B-NS3 protease, while maintaining their enzyme inhibitory activity and antiviral activity.

ACS Style

Youhei Takagi; Kouhei Matsui; Haruaki Nobori; Haruka Maeda; Akihiko Sato; Takeshi Kurosu; Yasuko Orba; Hirofumi Sawa; Kazunari Hattori; Kenichi Higashino; Yoshito Numata; Yutaka Yoshida. Discovery of novel cyclic peptide inhibitors of dengue virus NS2B-NS3 protease with antiviral activity. Bioorganic & Medicinal Chemistry Letters 2017, 27, 3586 -3590.

AMA Style

Youhei Takagi, Kouhei Matsui, Haruaki Nobori, Haruka Maeda, Akihiko Sato, Takeshi Kurosu, Yasuko Orba, Hirofumi Sawa, Kazunari Hattori, Kenichi Higashino, Yoshito Numata, Yutaka Yoshida. Discovery of novel cyclic peptide inhibitors of dengue virus NS2B-NS3 protease with antiviral activity. Bioorganic & Medicinal Chemistry Letters. 2017; 27 (15):3586-3590.

Chicago/Turabian Style

Youhei Takagi; Kouhei Matsui; Haruaki Nobori; Haruka Maeda; Akihiko Sato; Takeshi Kurosu; Yasuko Orba; Hirofumi Sawa; Kazunari Hattori; Kenichi Higashino; Yoshito Numata; Yutaka Yoshida. 2017. "Discovery of novel cyclic peptide inhibitors of dengue virus NS2B-NS3 protease with antiviral activity." Bioorganic & Medicinal Chemistry Letters 27, no. 15: 3586-3590.

Journal article
Published: 01 March 2017 in Antiviral Research
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High morbidity and mortality associated with human cases of highly pathogenic avian influenza (HPAI) viruses, including H5N1 influenza virus, have been reported. The purpose of the present study was to evaluate the antiviral effects of peramivir against HPAI viruses. In neuraminidase (NA) inhibition and virus replication inhibition assays, peramivir showed strong inhibitory activity against H5N1, H7N1 and H7N7 HPAI viruses with sub-nanomolar activity in enzyme assays. In H5N1 viruses containing the NA H275Y mutation, the antiviral activity of peramivir against the variant was lower than that against the wild-type. Evaluation of the in vivo antiviral activity showed that a single intravenous treatment of peramivir (10 mg/kg) prevented lethality in mice infected with wild-type H5N1 virus and also following infection with H5N1 virus with the H275Y mutation after a 5 day administration of peramivir (30 mg/kg). Furthermore, mice injected with peramivir showed low viral titers and low levels of proinflammatory cytokines in the lungs. These results suggest that peramivir has therapeutic activity against HPAI viruses even if the virus harbors the NA H275Y mutation.

ACS Style

Masanori Kobayashi; Makoto Kodama; Takeshi Noshi; Ryu Yoshida; Takushi Kanazu; Naoki Nomura; Kosuke Soda; Norikazu Isoda; Masatoshi Okamatsu; Yoshihiro Sakoda; Yoshinori Yamano; Akihiko Sato; Hiroshi Kida. Therapeutic efficacy of peramivir against H5N1 highly pathogenic avian influenza viruses harboring the neuraminidase H275Y mutation. Antiviral Research 2017, 139, 41 -48.

AMA Style

Masanori Kobayashi, Makoto Kodama, Takeshi Noshi, Ryu Yoshida, Takushi Kanazu, Naoki Nomura, Kosuke Soda, Norikazu Isoda, Masatoshi Okamatsu, Yoshihiro Sakoda, Yoshinori Yamano, Akihiko Sato, Hiroshi Kida. Therapeutic efficacy of peramivir against H5N1 highly pathogenic avian influenza viruses harboring the neuraminidase H275Y mutation. Antiviral Research. 2017; 139 ():41-48.

Chicago/Turabian Style

Masanori Kobayashi; Makoto Kodama; Takeshi Noshi; Ryu Yoshida; Takushi Kanazu; Naoki Nomura; Kosuke Soda; Norikazu Isoda; Masatoshi Okamatsu; Yoshihiro Sakoda; Yoshinori Yamano; Akihiko Sato; Hiroshi Kida. 2017. "Therapeutic efficacy of peramivir against H5N1 highly pathogenic avian influenza viruses harboring the neuraminidase H275Y mutation." Antiviral Research 139, no. : 41-48.

Journal article
Published: 01 May 2015 in Antiviral Research
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Influenza virus infection increases susceptibility to bacterial infection and mortality in humans. Although the efficacy of approved intravenous peramivir, a neuraminidase (NA) inhibitor, against influenza virus infection has been reported, its efficacy against bacterial co-infection, which occurs during the period of viral shedding, was not fully investigated. To further understand the significance of treatment with peramivir, we assessed the efficacy of peramivir against a bacterial co-infection model in mice caused by clinically isolated influenza A(H1N1)pdm09 virus and Streptococcus pneumoniae.

ACS Style

Motoyasu Onishi; Mitsutaka Kitano; Keiichi Taniguchi; Tomoyuki Homma; Masanori Kobayashi; Tomokazu Yoshinaga; Akira Naito; Akihiko Sato. Intravenous peramivir inhibits viral replication, and leads to bacterial clearance and prevention of mortality during murine bacterial co-infection caused by influenza A(H1N1)pdm09 virus and Streptococcus pneumoniae. Antiviral Research 2015, 117, 52 -59.

AMA Style

Motoyasu Onishi, Mitsutaka Kitano, Keiichi Taniguchi, Tomoyuki Homma, Masanori Kobayashi, Tomokazu Yoshinaga, Akira Naito, Akihiko Sato. Intravenous peramivir inhibits viral replication, and leads to bacterial clearance and prevention of mortality during murine bacterial co-infection caused by influenza A(H1N1)pdm09 virus and Streptococcus pneumoniae. Antiviral Research. 2015; 117 ():52-59.

Chicago/Turabian Style

Motoyasu Onishi; Mitsutaka Kitano; Keiichi Taniguchi; Tomoyuki Homma; Masanori Kobayashi; Tomokazu Yoshinaga; Akira Naito; Akihiko Sato. 2015. "Intravenous peramivir inhibits viral replication, and leads to bacterial clearance and prevention of mortality during murine bacterial co-infection caused by influenza A(H1N1)pdm09 virus and Streptococcus pneumoniae." Antiviral Research 117, no. : 52-59.

Journal article
Published: 01 September 2014 in Antiviral Research
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The purpose of this study was to investigate the relationship between pharmacokinetic (PK) parameters of intravenous (IV) peramivir and in vivo antiviral activity pharmacodynamic (PD) outcomes in a mouse model of influenza virus infection. Peramivir was administrated to mice in three dosing schedules; once, twice and four times after infection of A/WS/33 (H1N1). The survival rate at day 14 after virus infection was employed as the antiviral activity outcome for analysis. The relationship between day 14 survival and PK parameters, including area under the concentration-time curve (AUC), maximum concentration (Cmax) and time that drug concentration exceeds IC95 (T(>IC95)), was estimated using a logistic regression model, and model fitness was evaluated by calculation of the Akaike information criterion (AIC) index. The AIC indices of AUC, Cmax and T(>IC95) were about 114, 151 and 124, respectively. The AIC of AUC and T(>IC95) were smaller than that of Cmax. Therefore, both AUC and T(>IC95) were the PK parameters that correlated best with the antiviral activity of peramivir IV against influenza virus infection in mice.

ACS Style

Makoto Kodama; Ryu Yoshida; Takahiro Hasegawa; Masaaki Izawa; Mitsutaka Kitano; Kaoru Baba; Takeshi Noshi; Takahiro Seki; Kenichi Okazaki; Masakatsu Tsuji; Takushi Kanazu; Hiroshi Kamimori; Tomoyuki Homma; Masanori Kobayashi; Yoshihiro Sakoda; Hiroshi Kida; Akihiko Sato; Yoshinori Yamano. The relationship between in vivo antiviral activity and pharmacokinetic parameters of peramivir in influenza virus infection model in mice. Antiviral Research 2014, 109, 110 -115.

AMA Style

Makoto Kodama, Ryu Yoshida, Takahiro Hasegawa, Masaaki Izawa, Mitsutaka Kitano, Kaoru Baba, Takeshi Noshi, Takahiro Seki, Kenichi Okazaki, Masakatsu Tsuji, Takushi Kanazu, Hiroshi Kamimori, Tomoyuki Homma, Masanori Kobayashi, Yoshihiro Sakoda, Hiroshi Kida, Akihiko Sato, Yoshinori Yamano. The relationship between in vivo antiviral activity and pharmacokinetic parameters of peramivir in influenza virus infection model in mice. Antiviral Research. 2014; 109 ():110-115.

Chicago/Turabian Style

Makoto Kodama; Ryu Yoshida; Takahiro Hasegawa; Masaaki Izawa; Mitsutaka Kitano; Kaoru Baba; Takeshi Noshi; Takahiro Seki; Kenichi Okazaki; Masakatsu Tsuji; Takushi Kanazu; Hiroshi Kamimori; Tomoyuki Homma; Masanori Kobayashi; Yoshihiro Sakoda; Hiroshi Kida; Akihiko Sato; Yoshinori Yamano. 2014. "The relationship between in vivo antiviral activity and pharmacokinetic parameters of peramivir in influenza virus infection model in mice." Antiviral Research 109, no. : 110-115.

Journal article
Published: 01 May 2014 in Vaccine
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Synthetic hemozoin (sHZ, also known as β-hematin) from monomeric heme is a particle adjuvant which activates antigen-presenting cells (APCs), such as dendritic cells and macrophages, and enhances humoral immune responses to several antigens, including ovalbumin, human serum albumin, and serine repeat antigen 36 of Plasmodium falciparum. In the present study, we evaluated the adjuvanticity and pyrogenicity of sHZ as an adjuvant for seasonal trivalent hemagglutinin split vaccine (SV) for humans using the experimental ferret model.

ACS Style

Motoyasu Onishi; Mitsutaka Kitano; Keiichi Taniguchi; Tomoyuki Homma; Masanori Kobayashi; Akihiko Sato; Cevayir Coban; Ken J. Ishii. Hemozoin is a potent adjuvant for hemagglutinin split vaccine without pyrogenicity in ferrets. Vaccine 2014, 32, 3004 -3009.

AMA Style

Motoyasu Onishi, Mitsutaka Kitano, Keiichi Taniguchi, Tomoyuki Homma, Masanori Kobayashi, Akihiko Sato, Cevayir Coban, Ken J. Ishii. Hemozoin is a potent adjuvant for hemagglutinin split vaccine without pyrogenicity in ferrets. Vaccine. 2014; 32 (25):3004-3009.

Chicago/Turabian Style

Motoyasu Onishi; Mitsutaka Kitano; Keiichi Taniguchi; Tomoyuki Homma; Masanori Kobayashi; Akihiko Sato; Cevayir Coban; Ken J. Ishii. 2014. "Hemozoin is a potent adjuvant for hemagglutinin split vaccine without pyrogenicity in ferrets." Vaccine 32, no. 25: 3004-3009.

Journal article
Published: 01 May 2013 in Antimicrobial Agents and Chemotherapy
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The efficacy of intravenous peramivir against influenza A (H1N1) 2009 virus infection was evaluated in mice in which the immune system was suppressed by cyclophosphamide (CP) treatment. The mortality rate of the vehicle control group was 100%, and the mice lost 20% of their body weight on average by day 13 postinfection (p.i.). Repeated administration of peramivir (40 mg/kg of body weight once a day, given intravenously for 20 days), starting at 1 h p.i., significantly reduced mortality, body weight loss, viral titers, and cytokine production in infected mice compared with results for administration of vehicle ( P < 0.01). In addition, repeated administration of peramivir, starting at 24 h, 48 h, or 72 h p.i., also resulted in increases in survival rates and reduction of viral titers in the lungs ( P < 0.01). The mean days to death (MDD) of the vehicle group was 14.5 days, while in the groups treated with peramivir starting at 24 h, 48 h, and 72 h p.i., the MDDs were >23.0, 20.9, and 21.8 days, respectively. In comparison, repeated administration of oseltamivir phosphate (5 mg/kg twice a day, given orally for 20 days), starting at 24 h, 48 h, and 72 h p.i., also significantly prevented body weight loss, whereas no significant differences in mortality rates and viral titers in the lungs were observed compared with results for the vehicle group. These data indicated that repeated administration of peramivir was effective in promoting the survival and reducing virus replication in immunosuppressed mice infected with influenza A (H1N1) 2009 virus.

ACS Style

Mitsutaka Kitano; Makoto Kodama; Yasushi Itoh; Takushi Kanazu; Masanori Kobayashi; Ryu Yoshida; Akihiko Sato. Efficacy of Repeated Intravenous Injection of Peramivir against Influenza A (H1N1) 2009 Virus Infection in Immunosuppressed Mice. Antimicrobial Agents and Chemotherapy 2013, 57, 2286 -2294.

AMA Style

Mitsutaka Kitano, Makoto Kodama, Yasushi Itoh, Takushi Kanazu, Masanori Kobayashi, Ryu Yoshida, Akihiko Sato. Efficacy of Repeated Intravenous Injection of Peramivir against Influenza A (H1N1) 2009 Virus Infection in Immunosuppressed Mice. Antimicrobial Agents and Chemotherapy. 2013; 57 (5):2286-2294.

Chicago/Turabian Style

Mitsutaka Kitano; Makoto Kodama; Yasushi Itoh; Takushi Kanazu; Masanori Kobayashi; Ryu Yoshida; Akihiko Sato. 2013. "Efficacy of Repeated Intravenous Injection of Peramivir against Influenza A (H1N1) 2009 Virus Infection in Immunosuppressed Mice." Antimicrobial Agents and Chemotherapy 57, no. 5: 2286-2294.

Journal article
Published: 22 January 2013 in Journal of Medicinal Chemistry
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Takashi Kawasuji; Brian A. Johns; Hiroshi Yoshida; Jason G. Weatherhead; Toshiyuki Akiyama; Teruhiko Taishi; Yoshiyuki Taoda; Minako Mikamiyama-Iwata; Hitoshi Murai; Ryuichi Kiyama; Masahiro Fuji; Norihiko Tanimoto; Tomokazu Yoshinaga; Takahiro Seki; Masanori Kobayashi; Akihiko Sato; Edward P. Garvey; Tamio Fujiwara. Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles. Journal of Medicinal Chemistry 2013, 56, 1124 -1135.

AMA Style

Takashi Kawasuji, Brian A. Johns, Hiroshi Yoshida, Jason G. Weatherhead, Toshiyuki Akiyama, Teruhiko Taishi, Yoshiyuki Taoda, Minako Mikamiyama-Iwata, Hitoshi Murai, Ryuichi Kiyama, Masahiro Fuji, Norihiko Tanimoto, Tomokazu Yoshinaga, Takahiro Seki, Masanori Kobayashi, Akihiko Sato, Edward P. Garvey, Tamio Fujiwara. Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles. Journal of Medicinal Chemistry. 2013; 56 (3):1124-1135.

Chicago/Turabian Style

Takashi Kawasuji; Brian A. Johns; Hiroshi Yoshida; Jason G. Weatherhead; Toshiyuki Akiyama; Teruhiko Taishi; Yoshiyuki Taoda; Minako Mikamiyama-Iwata; Hitoshi Murai; Ryuichi Kiyama; Masahiro Fuji; Norihiko Tanimoto; Tomokazu Yoshinaga; Takahiro Seki; Masanori Kobayashi; Akihiko Sato; Edward P. Garvey; Tamio Fujiwara. 2013. "Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles." Journal of Medicinal Chemistry 56, no. 3: 1124-1135.

Journal article
Published: 01 February 2012 in Virology
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Attempts to find a cure for HIV infection are hindered by the presence of viral reservoirs that resist highly active antiretroviral therapy. To identify the properties of these reservoirs, four SIV239-infected Rhesus macaques were treated with combined antiretroviral therapy (cART) for 1year. While plasma viral RNA (vRNA) was effectively suppressed, a systemic analysis revealed that vRNA was distributed in the following order: lymphatic tissues>lungs and intestine>other tissues. Histochemistry yielded no cells with viral signals. To increase the chance of detection, two additional SIV-infected animals were treated and analyzed on Day 10 after the cessation of cART. These animals exhibited similar vRNA distribution patterns to the former animals, and immunohistochemistry revealed Nef-positive T lymphocytes predominantly in the follicles of mesenteric lymph nodes (MLNs). These data suggest that lymphatic tissues, including MLNs, contain major cellular reservoirs that cause rebound of plasma viremia upon cessation of therapy

ACS Style

Mariko Horiike; Shingo Iwami; Makoto Kodama; Akihiko Sato; Yuji Watanabe; Mika Yasui; Yuki Ishida; Takeshi Kobayashi; Tomoyuki Miura; Tatsuhiko Igarashi. Lymph nodes harbor viral reservoirs that cause rebound of plasma viremia in SIV-infected macaques upon cessation of combined antiretroviral therapy. Virology 2012, 423, 107 -118.

AMA Style

Mariko Horiike, Shingo Iwami, Makoto Kodama, Akihiko Sato, Yuji Watanabe, Mika Yasui, Yuki Ishida, Takeshi Kobayashi, Tomoyuki Miura, Tatsuhiko Igarashi. Lymph nodes harbor viral reservoirs that cause rebound of plasma viremia in SIV-infected macaques upon cessation of combined antiretroviral therapy. Virology. 2012; 423 (2):107-118.

Chicago/Turabian Style

Mariko Horiike; Shingo Iwami; Makoto Kodama; Akihiko Sato; Yuji Watanabe; Mika Yasui; Yuki Ishida; Takeshi Kobayashi; Tomoyuki Miura; Tatsuhiko Igarashi. 2012. "Lymph nodes harbor viral reservoirs that cause rebound of plasma viremia in SIV-infected macaques upon cessation of combined antiretroviral therapy." Virology 423, no. 2: 107-118.

Journal article
Published: 15 August 2011 in Antimicrobial Agents and Chemotherapy
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We evaluated the efficacy of a single intravenous dose peramivir for treatment of influenza B virus infection in ferrets and cynomolgus macaques in the present study. A single dose of peramivir (60 mg/kg of body weight) given to ferrets on 1 day postinfection with influenza B virus significantly reduced median area under the curve (AUC) virus titers (peramivir, 8.3 log1050% tissue culture infective doses [TCID50s]·day/ml; control, 10.7 log10TCID50s·day/ml;P< 0.0001). Furthermore, nasal virus titers on day 2 postinfection in ferrets receiving a single injection of peramivir (30 mg/kg) and AUCs of the body temperature increase in ferrets receiving a single injection of peramivir (30 and 60 mg/kg) were lower than those in ferrets administered oral oseltamivir phosphate (30 and 60 mg/kg/day twice daily for 3 days). In macaques infected with influenza B virus, viral titers in the nasal swab fluid on days 2 and 3 postinfection and body temperature after a single injection of peramivir (30 mg/kg) were lower than those after oral administration of oseltamivir phosphate (30 mg/kg/day for 5 days). The two animal models used in the present study demonstrated that inhibition of viral replication at the early time point after infection was critical in reduction of AUCs of virus titers and interleukin-6 production, resulting in amelioration of symptoms. Our results shown in animal models suggest that the early treatment with a single intravenous injection of peramivir is clinically recommended to reduce symptoms effectively in influenza B virus infection.

ACS Style

Mitsutaka Kitano; Yasushi Itoh; Makoto Kodama; Hirohito Ishigaki; Misako Nakayama; Hideaki Ishida; Kaoru Baba; Takahiro Noda; Kenji Sato; Yoichiro Nihashi; Takushi Kanazu; Ryu Yoshida; Ryuzo Torii; Akihiko Sato; Kazumasa Ogasawara. Efficacy of Single Intravenous Injection of Peramivir against Influenza B Virus Infection in Ferrets and Cynomolgus Macaques. Antimicrobial Agents and Chemotherapy 2011, 55, 4961 -4970.

AMA Style

Mitsutaka Kitano, Yasushi Itoh, Makoto Kodama, Hirohito Ishigaki, Misako Nakayama, Hideaki Ishida, Kaoru Baba, Takahiro Noda, Kenji Sato, Yoichiro Nihashi, Takushi Kanazu, Ryu Yoshida, Ryuzo Torii, Akihiko Sato, Kazumasa Ogasawara. Efficacy of Single Intravenous Injection of Peramivir against Influenza B Virus Infection in Ferrets and Cynomolgus Macaques. Antimicrobial Agents and Chemotherapy. 2011; 55 (11):4961-4970.

Chicago/Turabian Style

Mitsutaka Kitano; Yasushi Itoh; Makoto Kodama; Hirohito Ishigaki; Misako Nakayama; Hideaki Ishida; Kaoru Baba; Takahiro Noda; Kenji Sato; Yoichiro Nihashi; Takushi Kanazu; Ryu Yoshida; Ryuzo Torii; Akihiko Sato; Kazumasa Ogasawara. 2011. "Efficacy of Single Intravenous Injection of Peramivir against Influenza B Virus Infection in Ferrets and Cynomolgus Macaques." Antimicrobial Agents and Chemotherapy 55, no. 11: 4961-4970.

Journal article
Published: 29 November 2010 in Antimicrobial Agents and Chemotherapy
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S/GSK1349572 is a next-generation HIV integrase (IN) inhibitor designed to deliver potent antiviral activity with a low-milligram once-daily dose requiring no pharmacokinetic (PK) booster. In addition, S/GSK1349572 demonstrates activity against clinically relevant IN mutant viruses and has potential for a high genetic barrier to resistance. S/GSK1349572 is a two-metal-binding HIV integrase strand transfer inhibitor whose mechanism of action was established throughin vitrointegrase enzyme assays, resistance passage experiments, activity against viral strains resistant to other classes of anti-HIV agents, and mechanistic cellular assays. In a variety of cellular antiviral assays, S/GSK1349572 inhibited HIV replication with low-nanomolar or subnanomolar potency and with a selectivity index of 9,400. The protein-adjusted half-maximal effective concentration (PA-EC50) extrapolated to 100% human serum was 38 nM. When virus was passaged in the presence of S/GSK1349572, highly resistant mutants were not selected, but mutations that effected a low fold change (FC) in the EC50(up to 4.1 fold) were identified in the vicinity of the integrase active site. S/GSK1349572 demonstrated activity against site-directed molecular clones containing the raltegravir-resistant signature mutations Y143R, Q148K, N155H, and G140S/Q148H (FCs, 1.4, 1.1, 1.2, and 2.6, respectively), while these mutants led to a high FC in the EC50of raltegravir (11- to >130-fold). Either additive or synergistic effects were observed when S/GSK1349572 was tested in combination with representative approved antiretroviral agents; no antagonistic effects were seen. These findings demonstrate that S/GSK1349572 would be classified as a next-generation drug in the integrase inhibitor class, with a resistance profile markedly different from that of first-generation integrase inhibitors.

ACS Style

Masanori Kobayashi; Tomokazu Yoshinaga; Takahiro Seki; Chiaki Wakasa-Morimoto; Kevin W. Brown; Robert Ferris; Scott A. Foster; Richard J. Hazen; Shigeru Miki; Akemi Suyama-Kagitani; Shinobu Kawauchi-Miki; Teruhiko Taishi; Takashi Kawasuji; Brian A. Johns; Mark R. Underwood; Edward P. Garvey; Akihiko Sato; Tamio Fujiwara. In VitroAntiretroviral Properties of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor. Antimicrobial Agents and Chemotherapy 2010, 55, 813 -821.

AMA Style

Masanori Kobayashi, Tomokazu Yoshinaga, Takahiro Seki, Chiaki Wakasa-Morimoto, Kevin W. Brown, Robert Ferris, Scott A. Foster, Richard J. Hazen, Shigeru Miki, Akemi Suyama-Kagitani, Shinobu Kawauchi-Miki, Teruhiko Taishi, Takashi Kawasuji, Brian A. Johns, Mark R. Underwood, Edward P. Garvey, Akihiko Sato, Tamio Fujiwara. In VitroAntiretroviral Properties of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor. Antimicrobial Agents and Chemotherapy. 2010; 55 (2):813-821.

Chicago/Turabian Style

Masanori Kobayashi; Tomokazu Yoshinaga; Takahiro Seki; Chiaki Wakasa-Morimoto; Kevin W. Brown; Robert Ferris; Scott A. Foster; Richard J. Hazen; Shigeru Miki; Akemi Suyama-Kagitani; Shinobu Kawauchi-Miki; Teruhiko Taishi; Takashi Kawasuji; Brian A. Johns; Mark R. Underwood; Edward P. Garvey; Akihiko Sato; Tamio Fujiwara. 2010. "In VitroAntiretroviral Properties of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor." Antimicrobial Agents and Chemotherapy 55, no. 2: 813-821.

Journal article
Published: 17 April 2009 in Journal of Medicinal Chemistry
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The medicinal chemistry and structure-activity relationships for a novel series of 7-benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV-integrase inhibitors are disclosed. Substituent effects were evaluated at the N-1, C-3, and 7-benzyl positions of the naphthyridinone ring system. Low nanomolar IC(50) values were achieved in an HIV-integrase strand transfer assay with both carboxylic ester and carboxamide groups at C-3. More importantly, several carboxamide congeners showed potent antiviral activity in cellular assays. A 7-benzyl substituent was found to be critical for potent enzyme inhibition, and an N-(2-methoxyethyl)carboxamide moiety at C-3 significantly reduced plasma protein binding effects in vitro. Pharmacokinetic data in rats for one carboxamide analogue demonstrated oral bioavailability and reasonable in vivo clearance.

ACS Style

Eric E. Boros; Cynthia E. Edwards; Scott A. Foster; Masahiro Fuji; Tamio Fujiwara; Edward P. Garvey; Pamela L. Golden; Richard J. Hazen; Jerry L. Jeffrey; Brian A. Johns; Takashi Kawasuji; Ryuichi Kiyama; Cecilia S. Koble; Noriyuki Kurose; Wayne H. Miller; Angela L. Mote; Hitoshi Murai; Akihiko Sato; James B. Thompson; Mark C. Woodward; Tomokazu Yoshinaga. Synthesis and Antiviral Activity of 7-Benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV Integrase Inhibitors. Journal of Medicinal Chemistry 2009, 52, 2754 -2761.

AMA Style

Eric E. Boros, Cynthia E. Edwards, Scott A. Foster, Masahiro Fuji, Tamio Fujiwara, Edward P. Garvey, Pamela L. Golden, Richard J. Hazen, Jerry L. Jeffrey, Brian A. Johns, Takashi Kawasuji, Ryuichi Kiyama, Cecilia S. Koble, Noriyuki Kurose, Wayne H. Miller, Angela L. Mote, Hitoshi Murai, Akihiko Sato, James B. Thompson, Mark C. Woodward, Tomokazu Yoshinaga. Synthesis and Antiviral Activity of 7-Benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV Integrase Inhibitors. Journal of Medicinal Chemistry. 2009; 52 (9):2754-2761.

Chicago/Turabian Style

Eric E. Boros; Cynthia E. Edwards; Scott A. Foster; Masahiro Fuji; Tamio Fujiwara; Edward P. Garvey; Pamela L. Golden; Richard J. Hazen; Jerry L. Jeffrey; Brian A. Johns; Takashi Kawasuji; Ryuichi Kiyama; Cecilia S. Koble; Noriyuki Kurose; Wayne H. Miller; Angela L. Mote; Hitoshi Murai; Akihiko Sato; James B. Thompson; Mark C. Woodward; Tomokazu Yoshinaga. 2009. "Synthesis and Antiviral Activity of 7-Benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV Integrase Inhibitors." Journal of Medicinal Chemistry 52, no. 9: 2754-2761.

Journal article
Published: 28 February 2009 in Antiviral Research
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Passage of HIV-1 in the presence of integrase inhibitors (INIs) generates resistant viruses that have mutations in the integrase region. Integrase-resistant mutations Q148K and Q148R were identified as primary mutations with the passage of HIV-1 IIIB in the presence of INIs S-1360 or S/GSK-364735, respectively. Secondary amino acid substitutions E138K or G140S were observed when passage with INI was continued. The role of these mutations was investigated with molecular clones. Relative to Q148K alone, Q148K/E138K had 2- and >6-fold increases in resistance to S-1360 and S/GSK-364735, respectively, and the double mutant had slightly better infectivity and replication kinetics. In contrast, Q148K/G140S and Q148R/E138K had nearly equivalent or slightly reduced fold resistance to the INI compared with their respective Q148 primary mutants, and had increases in infectivity and replication kinetics. Recovery of these surrogates of viral fitness coincided with the recovery of integration efficiency of viral DNA into the host cell chromosome for these double mutants. These data show that recovery of viral integration efficiency can be an important factor for the emergence and maintenance of INI-resistant mutations.

ACS Style

Koichiro Nakahara; Chiaki Wakasa-Morimoto; Masanori Kobayashi; Shigeru Miki; Takeshi Noshi; Takahiro Seki; Mikiko Kanamori-Koyama; Shinobu Kawauchi; Akemi Suyama; Toshio Fujishita; Tomokazu Yoshinaga; Edward P. Garvey; Brian A. Johns; Scott A. Foster; Mark R. Underwood; Akihiko Sato; Tamio Fujiwara. Secondary mutations in viruses resistant to HIV-1 integrase inhibitors that restore viral infectivity and replication kinetics. Antiviral Research 2009, 81, 141 -146.

AMA Style

Koichiro Nakahara, Chiaki Wakasa-Morimoto, Masanori Kobayashi, Shigeru Miki, Takeshi Noshi, Takahiro Seki, Mikiko Kanamori-Koyama, Shinobu Kawauchi, Akemi Suyama, Toshio Fujishita, Tomokazu Yoshinaga, Edward P. Garvey, Brian A. Johns, Scott A. Foster, Mark R. Underwood, Akihiko Sato, Tamio Fujiwara. Secondary mutations in viruses resistant to HIV-1 integrase inhibitors that restore viral infectivity and replication kinetics. Antiviral Research. 2009; 81 (2):141-146.

Chicago/Turabian Style

Koichiro Nakahara; Chiaki Wakasa-Morimoto; Masanori Kobayashi; Shigeru Miki; Takeshi Noshi; Takahiro Seki; Mikiko Kanamori-Koyama; Shinobu Kawauchi; Akemi Suyama; Toshio Fujishita; Tomokazu Yoshinaga; Edward P. Garvey; Brian A. Johns; Scott A. Foster; Mark R. Underwood; Akihiko Sato; Tamio Fujiwara. 2009. "Secondary mutations in viruses resistant to HIV-1 integrase inhibitors that restore viral infectivity and replication kinetics." Antiviral Research 81, no. 2: 141-146.