Winkler Johannes
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
Ther Deliv. 2013 Jul;4(7):791-809. doi: 10.4155/tde.13.47.
Insufficient pharmacokinetic properties and poor cellular uptake are the main hurdles for successful therapeutic development of oligonucleotide agents. The covalent attachment of various ligands designed to influence the biodistribution and cellular uptake or for targeting specific tissues is an attractive possibility to advance therapeutic applications and to expand development options. In contrast to advanced formulations, which often consist of multiple reagents and are sensitive to a variety of preparation conditions, oligonucleotide conjugates are defined molecules, enabling structure-based analytics and quality control techniques. This review gives an overview of current developments of oligonucleotide conjugates for therapeutic applications. Attached ligands comprise peptides, proteins, carbohydrates, aptamers and small molecules, including cholesterol, tocopherol and folic acid. Important linkage types and conjugation methods are summarized. The distinct ligands directly influence biochemical parameters, uptake mechanisms and pharmacokinetic properties.
药代动力学性质不足和细胞摄取不佳是寡核苷酸药物成功用于治疗的主要障碍。设计各种用于影响生物分布和细胞摄取或靶向特定组织的配体共价连接，是推进治疗应用和扩大开发选择的一个有吸引力的可能性。与通常由多种试剂组成且对多种制备条件敏感的先进制剂不同，寡核苷酸缀合物是明确的分子，可实现基于结构的分析和质量控制技术。本综述概述了用于治疗应用的寡核苷酸缀合物的当前进展。连接的配体包括肽、蛋白质、碳水化合物、适体和小分子，包括胆固醇、生育酚和叶酸。总结了重要的连接类型和缀合方法。不同的配体直接影响生化参数、摄取机制和药代动力学性质。
