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) 是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核酸的潜力。因此，单链 ON 可以通过反义机制（即通过序列特异性结合 mRNA）抑制蛋白质生物合成，从而选择性调节基因产物。然而，ON 的潜在治疗应用受到重大障碍的阻碍。特别是，它们的药代动力学特性（细胞摄取和稳定性）不足，因此需要对ON的主链结构进行化学修饰。这导致了已经描述过的大量此类主链修饰。尽管在该领域取得了一些显着的成功，但这些修饰都没有成为药理学上有用的 ON 结构改变的普遍适用的工具。由于这些原因，我们讨论了 ON 前药概念的设计，以改善其药代动力学特性。因此，ON 的极性聚阴离子主链预计被亲脂性单元“掩蔽”，亲脂性单元在细胞摄取后被裂解以提供 ON（“化学特洛伊木马”原理）。在这个项目中，我们的目标是开发和研究具有潜在反义活性的单链ON的新型前药。因此，预计将从根本上促进具有治疗潜力的改良ON的开发。将建立新的 ON 前药的合成，并详细测试相应产品的药代动力学特性。此外，我们的目标是建立此类ON前药的细胞靶向，以便将它们开发成治疗上有用的反义剂。因此，我们将研究一种针对雌激素依赖性乳腺癌细胞的细胞特异性靶向的新方法，该方法基于低分子靶向单元与 ON 前药的缀合。总体目标是获得一种 ON 前药作为具有抗乳腺癌细胞活性的潜在候选药物。