title: Limited inhibitory effects of oseltamivir and zanamivir on human sialidases.
abstract: 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 (K(i), 3.7 +/- 0.48 and 12.9 +/- 0.07 microM, respectively), providing a contrast to the low nanomolar concentrations at which these drugs block the activity of the viral sialidases.
authors.affiliation: Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Hata
authors.forename: Koichi
authors.initials: K
authors.lastname: Koseki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Setsuko
authors.initials: S
authors.lastname: Moriya
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Sangchai
authors.initials: S
authors.lastname: Yingsakmongkon
authors.forename: Go
authors.initials: G
authors.lastname: Hirai
authors.forename: Mikiko
authors.initials: M
authors.lastname: Sodeoka
authors.forename: Mark
authors.initials: M
authors.lastname: von Itzstein
authors.forename: Taeko
authors.initials: T
authors.lastname: Miyagi
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D009975:Orthomyxoviridae / Q000201:enzymology; D053139:Oseltamivir / Q000009:adverse effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D053243:Zanamivir / Q000009:adverse effects*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053139:Oseltamivir; C486385:NEU1 protein, human; C403285:NEU2 protein, human; C491428:NEU4 protein, human; C465436:Neu3 protein, human; D009439:Neuraminidase; D053243:Zanamivir