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Antimicrobial Agents and Chemotherapy, December 2002, p. 3809-3816, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3809-3816.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mechanism by Which Mutations at His274 Alter Sensitivity of Influenza A Virus N1 Neuraminidase to Oseltamivir Carboxylate and Zanamivir

Michael Z. Wang,* Chun Y. Tai, and Dirk B. Mendel{dagger}

Gilead Sciences, Inc., Foster City, California 94404

Received 13 June 2002/ Returned for modification 29 August 2002/ Accepted 12 September 2002

Oseltamivir carboxylate is a potent and specific inhibitor of influenza neuraminidase (NA). An influenza A/H1N1 variant selected in vitro with reduced susceptibility to oseltamivir carboxylate contains a His274Tyr mutation. To understand the mechanism by which a His274Tyr mutation gives rise to drug resistance, we studied a series of NA variant proteins containing various substitutions at position 274. Replacement of His274 with larger side chain residues (Tyr or Phe) reduced the NA sensitivity to oseltamivir carboxylate. In contrast, replacement of His274 with smaller side chain residues (Gly, Asn, Ser, and Gln) resulted in enhanced or unchanged sensitivity to oseltamivir carboxylate. Previous studies have suggested that the slow-binding inhibition of NA by oseltamivir carboxylate is a result of the reorientation of Glu276. Loss of this slow-binding inhibition in the His274Tyr and His274Phe mutant NA but not in His274Asn, His274Gly, His274Ser, or His274Gln supports the conclusion that the conformational change of Glu276 is restricted in the His274Tyr and His274Phe mutant NA upon oseltamivir carboxylate binding. Interestingly, His274Asn, as well as His274Gly, His274Ser, and His274Gln, also displayed reduced sensitivity to zanamivir and its analogue, 4-amino-Neu5Ac2en. Substitution of His274 with Tyr in influenza A/Tokyo/3/67 (H3N2) recombinant NA did not affect the susceptibility to oseltamivir carboxylate. These data indicate that the volume occupied by the amino acid side chain at position 274 can influence the sensitivities of influenza N1 NA but not of N2 NA to both oseltamivir carboxylate and zanamivir.

* Corresponding author. Mailing address: Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404. Phone: (650) 522-5443. Fax: (650) 522-5890. E-mail: Michael_Wang{at}gilead.com.

{dagger} Present address: Sugen, South San Francisco, CA 94080.

Antimicrobial Agents and Chemotherapy, December 2002, p. 3809-3816, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3809-3816.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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