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Antimicrobial Agents and Chemotherapy, October 2008, p. 3484-3491, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00344-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Limited Inhibitory Effects of Oseltamivir and Zanamivir on Human Sialidases{triangledown}

Keiko Hata,1,2 Koichi Koseki,1,2 Kazunori Yamaguchi,1,2 Setsuko Moriya,1,2 Yasuo Suzuki,2,3,4 Sangchai Yingsakmongkon,3 Go Hirai,5 Mikiko Sodeoka,5 Mark von Itzstein,6 and Taeko Miyagi1,2*

Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293,1 CREST, Japan Science and Technology Agency, Kawaguchi-shi, Saitama,2 Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi 487-8501,3 Global COE Program for Innovation in Human Health Sciences, Yada, Shizuoka 422-8526,4 Synthetic Organic Chemistry Laboratory, RIKEN, Hirosawa, Wako 351-0198, Japan,5 Institute for Glycomics, Griffith University (Gold Coast Campus), PMB 50 Gold Coast Mail Centre, Queensland 9726, Australia6

Received 11 March 2008/ Returned for modification 30 May 2008/ Accepted 31 July 2008

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.

* Corresponding author. Mailing address: Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan. Phone: 81-22-384-3151. Fax: 81-22-381-1195. E-mail: miyagi-ta173{at}pref.miyagi.jp

{triangledown} Published ahead of print on 11 August 2008.

Antimicrobial Agents and Chemotherapy, October 2008, p. 3484-3491, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00344-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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