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Antimicrobial Agents and Chemotherapy, August 2002, p. 2602-2605, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2602-2605.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Novel Nucleoside Analogue MCC-478 (LY582563) Is Effective against Wild-Type or Lamivudine-Resistant Hepatitis B Virus

Suzane Kioko Ono-Nita,^1,2 Naoya Kato,^1* Yasushi Shiratori,¹ Flair José Carrilho,² and Masao Omata¹

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan,¹ Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo CEP 05403-000, Brazil²

Received 2 January 2002/ Returned for modification 11 February 2002/ Accepted 13 May 2002

The emergence of resistant hepatitis B virus (HBV) with the L528M mutation and/or the M552V and M552I mutations in the polymerase gene following long-term lamivudine treatment is becoming an important clinical problem. The aim of this study was to investigate the susceptibility of wild-type and lamivudine-resistant HBV to MCC-478 (LY582563), a novel nucleoside analogue derivative of phosphonomethoxyethyl purine. The susceptibility of wild-type HBV and lamivudine-resistant mutants (M552I, M552V, and L528M/M552V) to MCC-478 was examined by transient transfection of full-length HBV DNA into human hepatoma cells. HBV DNA replication was monitored by Southern blot hybridization, and the effective concentration required to reduce replication by 50% (EC₅₀) was determined. The replicative intermediates of wild-type and lamivudine-resistant mutants were progressively diminished by treatment with increasing doses of MCC-478. The MCC-478 EC₅₀s were 0.027 µM for wild-type HBV (about 20 times more efficient than lamivudine), 2.6 µM for M552I, 3.3 µM for M552V, and 2.0 µM for L528M/M552V. Wild-type HBV and lamivudine-resistant mutants are susceptible to MCC-478. MCC-478 appears to be a candidate for the treatment of HBV infection and exhibits potent activity against lamivudine-resistant HBV.

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* Corresponding author. Mailing address: Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-3815-5411, ext. 37198. Fax: 81-3-3814-0021. E-mail: kato-2im{at}h.u-tokyo.ac.jp.

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Antimicrobial Agents and Chemotherapy, August 2002, p. 2602-2605, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2602-2605.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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