Ai-biopharma, Medicinal Chemistry Department, Montpellier, France.
Ai-biopharma, Medicinal Chemistry Department, Montpellier, France.
Antiviral Res. 2020 Jul;179:104815. doi: 10.1016/j.antiviral.2020.104815. Epub 2020 May 5.
Chronic Hepatitis B Virus infections afflict >250 million people and kill nearly 1 million annually. Current non-curative therapies are dominated by nucleos(t)ide analogs (NAs) that profoundly but incompletely suppress DNA synthesis by the viral reverse transcriptase. Residual HBV replication during NA therapy contributes to maintenance of the critical nuclear reservoir of the HBV genome, the covalently-closed circular DNA, and to ongoing infection of naive cells. Identification of next-generation NAs with improved efficacy and safety profiles, often through novel prodrug approaches, is the primary thrust of ongoing efforts to improve HBV replication inhibitors. Inhibitors of the HBV ribonuclease H, the other viral enzymatic activity essential for viral genomic replication, are in preclinical development. The complexity of HBV's reverse transcription pathway offers many other potential targets. HBV's protein-priming of reverse transcription has been briefly explored as a potential target, as have the host chaperones necessary for function of the HBV reverse transcriptase. Improved inhibitors of HBV reverse transcription would reduce HBV's replication-dependent persistence mechanisms and are therefore expected to become a backbone of future curative combination anti-HBV therapies.
慢性乙型肝炎病毒感染影响全球超过 2.5 亿人，并导致近 100 万人每年死亡。目前非治愈性疗法主要依赖于核苷（酸）类似物（NAs），这些药物可通过病毒逆转录酶深度但不完全抑制 DNA 合成。NA 治疗期间的 HBV 复制会导致 HBV 基因组的关键核储存库（共价闭合环状 DNA）持续存在，并导致未感染细胞的持续感染。通过新型前药方法等，提高下一代 NAs 的疗效和安全性谱，是提高 HBV 复制抑制剂的主要努力方向。HBV 核糖核酸酶 H 的抑制剂，即另一种对病毒基因组复制至关重要的病毒酶活性抑制剂，正在进行临床前开发。HBV 逆转录途径的复杂性为许多其他潜在靶点提供了机会。HBV 的蛋白引发逆转录已被短暂探索作为一种潜在靶点，HBV 逆转录酶功能所必需的宿主伴侣蛋白也是如此。HBV 逆转录的改进抑制剂将降低 HBV 的复制依赖性持续存在机制，因此有望成为未来治愈性联合抗 HBV 疗法的基础。
