Chen Lei, Deng Mingzhenlong, Yan Wanli, Zeng Ziwei, Chen Di, Zhao Yonglong, Wu Yisong, Li Yan, He Bin
State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China.
Eur J Med Chem. 2025 Feb 15;284:117207. doi: 10.1016/j.ejmech.2024.117207. Epub 2024 Dec 24.
Hepatitis B virus (HBV) infection remains a significant global health challenge, often leading to severe liver complications such as cirrhosis and cancer. Current treatments rely heavily on nucleos(t)ide analogues like adefovir and tenofovir due to their potent antiviral effects. However, their clinical utility is limited by insufficient liver targeting, leading to off-target side effects, particularly nephrotoxicity. To improve liver-specific drug delivery and reduce adverse effects, we designed novel liver-targeted prodrugs by conjugating adefovir and tenofovir with N-acetylgalactosamine (GalNAc) and tris-GalNAc ligands, which have high affinity for the asialoglycoprotein receptor (ASGPR) predominantly expressed in hepatocytes. Four prodrugs (A1, A2, T1, and T2) were synthesized and evaluated for cytotoxicity, maximum tolerated dose, anti-HBV activity, metabolic stability, pharmacokinetics, and liver-targeting properties. The prodrugs exhibited low cytotoxicity, robust anti-HBV activity, and enhanced selectivity compared to their parent drugs. Notably, the tris-GalNAc conjugates A2 and T2 demonstrated superior liver targeting, showing a threefold higher concentration in the liver compared to the kidneys, thus minimizing renal exposure. These findings suggest that GalNAc and tris-GalNAc conjugation is a promising strategy for enhancing the therapeutic efficacy and safety of adefovir and tenofovir, with potential for further optimization as liver-targeted anti-HBV prodrugs.
乙型肝炎病毒（HBV）感染仍然是一项重大的全球健康挑战，常常导致严重的肝脏并发症，如肝硬化和癌症。由于其强大的抗病毒作用，目前的治疗严重依赖于阿德福韦和替诺福韦等核苷（酸）类似物。然而，它们的临床效用受到肝脏靶向性不足的限制，导致脱靶副作用，尤其是肾毒性。为了改善肝脏特异性药物递送并减少不良反应，我们通过将阿德福韦和替诺福韦与对主要在肝细胞中表达的去唾液酸糖蛋白受体（ASGPR）具有高亲和力的N-乙酰半乳糖胺（GalNAc）和三-GalNAc配体缀合，设计了新型肝脏靶向前药。合成了四种前药（A1、A2、T1和T2），并对其细胞毒性、最大耐受剂量、抗HBV活性、代谢稳定性、药代动力学和肝脏靶向特性进行了评估。与它们的母体药物相比，这些前药表现出低细胞毒性、强大的抗HBV活性和更高的选择性。值得注意的是，三-GalNAc缀合物A2和T2表现出卓越的肝脏靶向性，其在肝脏中的浓度比在肾脏中高两倍，从而使肾脏暴露最小化。这些发现表明，GalNAc和三-GalNAc缀合是提高阿德福韦和替诺福韦治疗效果和安全性的一种有前景的策略，具有作为肝脏靶向抗HBV前药进一步优化的潜力。
