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，是沃森和克里克在1953年首次提出的“扭曲梯子”结构。但是，尚不清楚DNA可以采用许多不同的形状。由于首先揭示了DNA的结构，因此许多研究表明，DNA采用了许多不同的形式，这些形式与其在生物学中所起的作用有关。 DNA由四个基础组成，通常被描述为生命的“构件”，因为它们编码了建造和维护生物所需的所有信息。这四个碱基（腺嘌呤，鸟嘌呤，胸腺嘧啶和胞嘧啶）的序列是将我们定义为人类的原因，使我们与细菌，酵母和植物不同。包含大量碱基的DNA序列可以形成替代的二级结构，而不是像正常的两条链的“扭曲梯子”一样，而是非常紧密的DNA链的“立方体”。我们称这些结构为g Quadruplexes。这种类型的序列在整个人类基因组中也广泛存在，存在于细胞中，并已被证明在基因表达中起作用并定义了我们的细胞寿命的时间。这些DNA序列在引起癌症的基因中比其他基因更重要，并且许多研究致力于设计类似药物样的化合物以靶向G四链体结构。尽管知识方面取得了这些进步，但尚未专门针对这些G-四链体结构。我们知道，可以通过将它们连接到抗体来使其对某些类型的细胞更为特异性，从而使其更具体。抗体 - 药物结合物是一类生物药物，可以用作治疗癌症等疾病的靶向疗法。通过将类似药物的分子与抗体联系起来，抗体将能够找到特定的患病细胞并留下健康的细胞。这使我们能够拥有一种仅针对需要治疗细胞的药物，例如癌症和健康细胞之间。重要的是，这种总体方法可以应用于许多不同的疾病和状况。该提案的核心目的是开发针对靶向G四链体DNA的化合物的抗体药物结合物。我们以前的工作使我们了解了将药物与抗体联系起来的策略和策略。我们拥有初步数据，可以显示不同的方法将药物与抗体连接起来。我们将开发抗体药物缀合物，表征它们的性质和专门释放其有效载荷的能力。该项目的结果和潜在影响将促进我们对如何将药物与抗体连接起来的理解（并且适用于其他生物分子）。这项工作还将以G-四链体结合化合物作为有效载荷开发第一种抗体药物结合物。结果将揭示一个新的抗体药物偶联家族，并采用将知识应用于其他系统的途径。