Limited inhibitory effects of oseltamivir and zanamivir on human sialidases

Keiko Hata, Koichi Koseki, Kazunori Yamaguchi, Setsuko Moriya, Yasuo Suzuki, Sangchai Yingsakmongkon, Go Hirai, Mikiko Sodeoka, Mark Von Itzstein, Taeko Miyagi

Research output: Contribution to journalArticlepeer-review

114 Citations (Scopus)

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 (Ki, 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.

Original languageEnglish
Pages (from-to)3484-3491
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume52
Issue number10
DOIs
Publication statusPublished - Oct 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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