Lipophilic prodrugs of oligonucleotides: synthesis, properties and conjugates for cellular targeting

寡核苷酸的亲脂性前药：细胞靶向的合成、特性和缀合物

• 批准号: 419032274
• 负责人: Professor Dr. Christian Ducho
• 金额: --
• 依托单位: Lehrstuhl für Pharmazeutische und Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/419032274?language=en
• 关键词: Lipophilic; prodrugs; oligonucleotides; synthesis; properties

Oligonucleotides (ON) represent attractive drug candidates as they display the potential to bind endogenous nucleic acids in a sequence-specific manner. Thus, single-stranded ON can inhibit protein biosynthesis via the antisense mechanism (i.e. via sequence-specific binding to mRNA), resulting in the selective modulation of a gene product. However, potential therapeutic applications of ON are hampered by significant hurdles. In particular, their pharmacokinetic properties (cellular uptake and stability) are insufficient, hence requiring the chemical modification of the backbone structure of ON. This has resulted in a significant number of such backbone modifications which have already been described. In spite of some remarkable success in this field, none of these modifications has become a universally applicable tool for a pharmacologically useful alteration of ON structures. For these reasons, the design of prodrug concepts for ON has been discussed in order to improve their pharmacokinetic properties. Thus, the polar polyanionic backbone of ON is envisioned to be 'masked' with lipophilic units, which are supposed to be cleaved after cellular uptake to provide the ON ('chemical Trojan horse' principle). In this project, we aim to develop and investigate novel prodrugs of single-stranded ON with potential antisense activity. Thereby, it is envisioned to fundamentally contribute to the development of modified ON with therapeutic potential. The synthesis of new ON prodrugs will be established, and the according products will be tested in detail for their pharmacokinetic properties. Furthermore, it is our goal to establish the cellular targeting of such ON prodrugs in order to develop them into therapeutically useful antisense agents. We will therefore study a novel approach for a cell-specific targeting of estrogen-dependent breast cancer cells, which is based on the conjugation of low-molecular targeting units with the ON prodrugs. The overall goal will be to obtain an ON prodrug as a potential drug candidate with activity against breast cancer cells.

寡核苷酸（ON）代表有吸引力的候选药物，因为它们显示出以序列特异性方式结合内源性核酸的潜力。因此，单链ON可以通过反义机制（即通过与mRNA的序列特异性结合）抑制蛋白质生物合成，导致基因产物的选择性调节。然而，ON的潜在治疗应用受到重大障碍的阻碍。特别是，它们的药代动力学性质（细胞摄取和稳定性）不足，因此需要对ON的骨架结构进行化学修饰。这导致了大量已经描述的这种骨架修饰。尽管在这一领域取得了一些显著的成功，但这些修饰中没有一个已经成为用于ON结构的非常规有用的改变的普遍适用的工具。由于这些原因，已经讨论了ON的前药概念的设计，以改善其药代动力学性质。因此，ON的极性聚阴离子主链被设想为被亲脂性单元“掩蔽”，亲脂性单元被认为在细胞摄取后被裂解以提供ON（“化学特洛伊木马”原理）。本研究旨在开发和研究具有潜在反义活性的单链ON前药。因此，设想从根本上有助于开发具有治疗潜力的修饰ON。将建立新的ON前药的合成，并将详细测试相应产物的药代动力学性质。此外，我们的目标是建立这种ON前药的细胞靶向，以便将它们开发成治疗上有用的反义试剂。因此，我们将研究一种细胞特异性靶向雌激素依赖性乳腺癌细胞的新方法，该方法基于低分子靶向单元与ON前药的缀合。总体目标将是获得作为具有抗乳腺癌细胞活性的潜在候选药物的ON前药。