DataSheet1_Expanding the toolbox of metabolically stable lipid prodrug strategies.docx

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside and nucleotide therapeutics, small context-dependent amendments to these popular prodrug strategies can drive dramatic improvements in pharmacokinetic (PK) profiles. Herein we offer a brief overview of current prodrug strategies, as well as a case study involving the fine-tuning of lipid prodrugs of acyclic nucleoside phosphonate tenofovir (TFV), an approved nucleotide HIV reverse transcriptase inhibitor (NtRTI) and the cornerstone of combination antiretroviral therapy (cART). Installation of novel lipid terminal motifs significantly reduced fatty acid hepatic ω-oxidation while maintaining potent antiviral activity. This work contributes important insights to the expanding repertoire of lipid prodrug strategies in general, but particularly for the delivery and distribution of acyclic nucleoside phosphonates.

核苷与核苷酸类治疗药物，是罹患恶性肿瘤与病毒性疾病患者不可或缺的治疗选择。此类药物通常以前药（prodrug）的形式给药于患者，以最大化生物利用度与治疗疗效。尽管现有文献已提供一套实用的前药开发指南，以助力核苷及核苷酸类治疗药物的递送，但对这些主流前药策略进行微小的情境依赖性调整，便可显著改善其药代动力学（pharmacokinetic, PK）特征。本文简要概述了当前主流的前药策略，并附带一则案例研究：针对无环核苷酸膦酸酯替诺福韦（acyclic nucleoside phosphonate tenofovir, TFV）的脂质前药开展优化调整。替诺福韦是一款已获批的核苷酸类HIV逆转录酶抑制剂（NtRTI），亦是联合抗逆转录病毒治疗（cART）的基石药物。研究表明，引入新型脂质末端基序可大幅降低脂肪酸的肝脏ω-氧化过程，同时保留强效的抗病毒活性。本研究不仅为日益丰富的脂质前药策略库提供了重要见解，尤其为无环核苷酸膦酸酯类药物的递送与分布研究提供了关键参考。