Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Sci Adv. 2022 Dec 23;8(51):eade9582. doi: 10.1126/sciadv.ade9582.
Treatment of chronic hepatitis B virus (HBV) requires lifelong daily therapy. However, suboptimal adherence to the existing daily therapy has led to the need for ultralong-acting antivirals. A lipophilic and hydrophobic ProTide was made by replacing the alanyl isopropyl ester present in tenofovir alafenamide (TAF) with a docosyl phenyl alanyl ester, now referred to as M1TFV. NM1TFV and nanoformulated TAF (NTAF) nanocrystals were formulated by high-pressure homogenization. A single intramuscular injection of NM1TFV, but not NTAF, delivered at a dose of TFV equivalents (168 milligrams per kilogram) demonstrated monthslong antiviral activities in both HBV-transgenic and human hepatocyte transplanted TK-NOG mice. The suppression of HBV DNA in blood was maintained for 3 months. Laboratory experiments on HBV-transfected HepG2.2.15 cells affirmed the animal results and the critical role of docosanol in the sustained NM1TFV antiviral responses. These results provide clear "proof of concept" toward an emerging therapeutic paradigm for the treatment and prevention of HBV infection.
治疗慢性乙型肝炎病毒 (HBV) 需要终身每日治疗。然而，由于现有每日治疗的依从性不佳，因此需要超长效抗病毒药物。通过用二十二烷苯基丙氨酸酯替代替诺福韦艾拉酚胺 (TAF) 中存在的丙氨酰异丙酯，制成了亲脂性和亲脂性的 ProTide，现在称为 M1TFV。通过高压匀质法制备了 NM1TFV 和纳米配方 TAF（NTAF）纳米晶体。NM1TFV（剂量为 TFV 等效物 168 毫克/千克）单次肌内注射，而不是 NTAF，在 HBV 转基因和人肝细胞移植 TK-NOG 小鼠中均显示出长达数月的抗病毒活性。血液中 HBV DNA 的抑制作用持续了 3 个月。在转染 HBV 的 HepG2.2.15 细胞的实验室实验中证实了动物实验结果以及二十二烷醇在持续 NM1TFV 抗病毒反应中的关键作用。这些结果为治疗和预防 HBV 感染的新兴治疗范例提供了明确的“概念验证”。
