Enabling The Targeted Delivery Of DNA G-quadruplex Ligands using a Novel Antibody DAR-1 Platform

使用新型抗体 DAR-1 平台实现 DNA G 四链体配体的靶向递送

• 批准号: BB/Y002180/1
• 负责人: Zoë Ann Ella Waller
• 金额: $ 71.72万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY002180%2F1
• 关键词: Enabling; Targeted; Delivery; DNA; quadruplex

DNA is often assumed to be a double helix, the "twisted ladder" structure which was first proposed by Watson and Crick in 1953. However, it is not widely known that DNA can adopt many different shapes. Since the structure of DNA was first revealed, much research has shown that DNA takes many different forms and these are related to the role it plays in biology. DNA is comprised of four bases, often described as the "building blocks" for life because they encode all the information required to build and maintain an organism. The sequence of these four bases (adenine, guanine, thymine and cytosine) is what defines us as humans and what makes us different to bacteria, yeast and plants. DNA sequences which contain lots of the base guanine can form alternative secondary structures which instead of appearing like the normal "twisted ladder" of two strands, are a very tightly packed "cube" of four strands of DNA. We call these structures G-quadruplexes. Sequences of this type are also widespread throughout the human genome, exist in cells and have been shown to play a role in gene expression and defining how long our cells live. These DNA sequences are found in cancer-causing genes more than other genes and a lot of research has been dedicated to designing drug-like compounds to target G-quadruplex structures. Despite these advances in knowledge, targeting these G-quadruplex structures specifically has not been achieved. We know that unspecific but potent compounds can be made more specific for certain types of cells by connecting them to antibodies. Antibody-drug conjugates are a class of biological drugs that can be used as a targeted therapy to treat conditions such as cancer. By connecting a drug-like molecule to an antibody, the antibody will be able to find the specific diseased cells and leave healthy cells alone. This enables us to have a drug that targets only the cells that need the treatment, for example between cancer and healthy cells. Importantly, this overall approach could be applied to many different diseases and conditions. The central aim of this proposal is to develop antibody drug conjugates for compounds that target G-quadruplex DNA. Our previous work has given us an understanding of strategies and tactics for connecting drugs to antibodies. We have preliminary data to show different ways to connect drugs to antibodies. We will develop antibody drug conjugates, characterise their properties and their ability to release their payload specifically to only diseased cells. The outcomes and potential impact of this project will advance our understanding of how to connect drugs to antibodies (and will be applicable to other biomolecules). The work will also develop the first antibody drug conjugate with a G-quadruplex binding compound as the payload. The outcomes will reveal a new family of antibody drug conjugates, with a pathway for applying the knowledge to other systems.

DNA 通常被认为是双螺旋，即“扭曲的梯子”结构，由 Watson 和 Crick 于 1953 年首次提出。然而，人们并不普遍知道 DNA 可以采用多种不同的形状。自从 DNA 结构首次被揭示以来，许多研究表明 DNA 有多种不同的形式，这些形式与其在生物学中所扮演的角色有关。 DNA 由四个碱基组成，通常被称为生命的“构建模块”，因为它们编码了构建和维持有机体所需的所有信息。这四种碱基（腺嘌呤、鸟嘌呤、胸腺嘧啶和胞嘧啶）的序列定义了我们人类，也使我们与细菌、酵母和植物不同。含有大量碱基鸟嘌呤的 DNA 序列可以形成替代的二级结构，它不像正常的两条链的“扭曲梯子”那样，而是一个非常紧密地堆积的四链 DNA 的“立方体”。我们将这些结构称为 G-四联体。这种类型的序列也广泛存在于整个人类基因组中，存在于细胞中，并且已被证明在基因表达和决定我们细胞寿命的过程中发挥作用。这些 DNA 序列在致癌基因中的发现量多于其他基因，并且大量研究致力于设计针对 G-四链体结构的药物样化合物。尽管知识取得了这些进步，但针对这些 G 四链体结构的具体目标尚未实现。我们知道，通过将某些类型的细胞与抗体连接，可以使非特异性但有效的化合物对某些类型的细胞更具特异性。抗体药物偶联物是一类生物药物，可用作治疗癌症等疾病的靶向疗法。通过将类药物分子连接到抗体上，抗体将能够找到特定的患病细胞，而不会影响健康细胞。这使我们能够拥有一种仅针对需要治疗的细胞的药物，例如癌症细胞和健康细胞之间的药物。重要的是，这种总体方法可以应用于许多不同的疾病和病症。该提案的中心目标是开发针对 G-四链体 DNA 的化合物的抗体药物缀合物。我们之前的工作使我们了解了将药物与抗体连接起来的策略和策略。我们有初步数据来展示将药物与抗体连接起来的不同方法。我们将开发抗体药物缀合物，表征它们的特性以及它们专门向患病细胞释放有效负载的能力。该项目的成果和潜在影响将增进我们对如何将药物与抗体连接起来的理解（并将适用于其他生物分子）。这项工作还将开发第一个以 G-四链体结合化合物作为有效负载的抗体药物缀合物。研究结果将揭示一个新的抗体药物偶联物家族，以及将这些知识应用到其他系统的途径。