对乙型肝炎病毒感染具有特异性的抗病毒L-核苷。
Antiviral L-nucleosides specific for hepatitis B virus infection.
作者信息
Bryant M L, Bridges E G, Placidi L, Faraj A, Loi A G, Pierra C, Dukhan D, Gosselin G, Imbach J L, Hernandez B, Juodawlkis A, Tennant B, Korba B, Cote P, Marion P, Cretton-Scott E, Schinazi R F, Sommadossi J P
机构信息
Novirio Pharmaceuticals, Inc., Cambridge, Massachusetts 02140, USA.
出版信息
Antimicrob Agents Chemother. 2001 Jan;45(1):229-35. doi: 10.1128/AAC.45.1.229-235.2001.
Abstract
A unique series of simple "unnatural" nucleosides has been discovered to inhibit hepatitis B virus (HBV) replication. Through structure-activity analysis it was found that the 3'-OH group of the beta-L-2'-deoxyribose of the beta-L-2'-deoxynucleoside confers specific antihepadnavirus activity. The unsubstituted nucleosides beta-L-2'-deoxycytidine, beta-L-thymidine, and beta-L-2'-deoxyadenosine had the most potent, selective, and specific antiviral activity against HBV replication. Human DNA polymerases (alpha, beta, and gamma) and mitochondrial function were not affected. In the woodchuck model of chronic HBV infection, viral load was reduced by as much as 10(8) genome equivalents/ml of serum and there was no drug-related toxicity. In addition, the decline in woodchuck hepatitis virus surface antigen paralleled the decrease in viral load. These investigational drugs, used alone or in combination, are expected to offer new therapeutic options for patients with chronic HBV infection.
摘要
已发现一系列独特的简单“非天然”核苷可抑制乙型肝炎病毒（HBV）复制。通过构效分析发现，β-L-2'-脱氧核苷的β-L-2'-脱氧核糖的3'-OH基团赋予了特异性抗嗜肝DNA病毒活性。未取代的核苷β-L-2'-脱氧胞苷、β-L-胸苷和β-L-2'-脱氧腺苷对HBV复制具有最强效、最具选择性和特异性的抗病毒活性。人DNA聚合酶（α、β和γ）及线粒体功能未受影响。在慢性HBV感染的土拨鼠模型中，病毒载量降低多达10(8)基因组当量/毫升血清，且无药物相关毒性。此外，土拨鼠肝炎病毒表面抗原的下降与病毒载量的减少平行。这些研究性药物单独使用或联合使用，有望为慢性HBV感染患者提供新的治疗选择。
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