Limited Inhibitory Effects of Oseltamivir and Zanamivir on Human Sialidases
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- Keiko Hata
- Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293
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- Koichi Koseki
- Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293
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- Kazunori Yamaguchi
- Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293
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- Setsuko Moriya
- Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293
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- Yasuo Suzuki
- CREST, Japan Science and Technology Agency, Kawaguchi-shi, Saitama
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- Sangchai Yingsakmongkon
- Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi 487-8501
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- Go Hirai
- Synthetic Organic Chemistry Laboratory, RIKEN, Hirosawa, Wako 351-0198, Japan
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- Mikiko Sodeoka
- Synthetic Organic Chemistry Laboratory, RIKEN, Hirosawa, Wako 351-0198, Japan
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- Mark von Itzstein
- Institute for Glycomics, Griffith University (Gold Coast Campus), PMB 50 Gold Coast Mail Centre, Queensland 9726, Australia
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- Taeko Miyagi
- Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293
説明
<jats:title>ABSTRACT</jats:title> <jats:p> Oseltamivir (Tamiflu) and zanamivir (Relenza), two extensively used clinically effective anti-influenza drugs, are viral sialidase (also known as neuraminidase) inhibitors that prevent the release of progeny virions and thereby limit the spread of infection. Recently mortalities and neuropsychiatric events have been reported with the use of oseltamivir, especially in pediatric cases in Japan, suggesting that these drugs might also inhibit endogenous enzymes involved in sialic acid metabolism, including sialidase, sialyltransferase, and CMP-synthase, in addition to their inhibitory effects on the viral sialidase. The possible inhibition could account for some of the rare side effects of oseltamivir. However, there has been little direct evidence in regard to the sensitivities of animal sialidases to these drugs. Here, we examined whether these inhibitors might indeed affect the activities of human sialidases, which differ in primary structures and enzyme properties but possess tertiary structures similar to those of the viral enzymes. Using recombinant enzymes corresponding to the four human sialidases identified so far, we found that oseltamivir carboxylate scarcely affected the activities of any of the sialidases, even at 1 mM, while zanamivir significantly inhibited the human sialidases NEU3 and NEU2 in the micromolar range ( <jats:italic> K <jats:sub>i</jats:sub> </jats:italic> , 3.7 ± 0.48 and 12.9 ± 0.07 μM, respectively), providing a contrast to the low nanomolar concentrations at which these drugs block the activity of the viral sialidases. </jats:p>
収録刊行物
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- Antimicrobial Agents and Chemotherapy
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Antimicrobial Agents and Chemotherapy 52 (10), 3484-3491, 2008-10
American Society for Microbiology
