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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Novel Nucleoside Analogue MCC-478 (LY582563) Is Effective against Wild-Type or Lamivudine-Resistant Hepatitis B Virus.
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Novel Nucleoside Analogue MCC-478 (LY582563) Is Effective against Wild-Type or Lamivudine-Resistant Hepatitis B Virus.

机译：新型核苷类似物MCC-478（LY582563）对野生型或抗拉米夫定的乙型肝炎病毒有效。

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摘要

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% (EC(50)) 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 EC(50)s were 0.027 microM for wild-type HBV (about 20 times more efficient than lamivudine), 2.6 microM for M552I, 3.3 microM for M552V, and 2.0 microM 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.
机译：长期接受拉米夫定治疗后，聚合酶基因中出现带有L528M突变和/或M552V和M552I突变的抗性乙型肝炎病毒（HBV）成为重要的临床问题。这项研究的目的是研究野生型和抗拉米夫定的HBV对MCC-478（LY582563）的敏感性，该化合物是膦酰基甲氧基乙基嘌呤的新型核苷类似物衍生物。通过将全长HBV DNA瞬时转染到人肝癌细胞中，检查了野生型HBV和拉米夫定耐药突变体（M552I，M552V和L528M / M552V）对MCC-478的敏感性。通过Southern blot杂交监测HBV DNA的复制，并确定减少复制50％所需的有效浓度（EC（50））。通过增加剂量的MCC-478处理，野生型和拉米夫定耐药突变体的复制中间体逐渐减少。 MCC-478 EC（50）的野生型HBV为0.027 microM（比拉米夫定高约20倍），M552I为2.6 microM，M552V为3.3 microM，L528M / M552V为2.0 microM。野生型HBV和抗拉米夫定的突变株对MCC-478敏感。 MCC-478似乎是治疗HBV感染的候选药物，并且具有抗拉米夫定耐药性HBV的强大活性。

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