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

DNA通常被认为是双螺旋，即“扭曲的梯子”结构，这是沃森和克里克在1953年首次提出的。然而，人们并不知道DNA可以采用许多不同的形状。自从DNA的结构首次被揭示以来，许多研究表明DNA有许多不同的形式，这些形式与它在生物学中所扮演的角色有关。DNA由四种碱基组成，通常被描述为生命的“基石”，因为它们编码了构建和维持生物体所需的所有信息。这四种碱基（腺嘌呤、鸟嘌呤、胸腺嘧啶和胞嘧啶）的序列是我们人类的定义，也是我们与细菌、酵母和植物不同的原因。含有大量鸟嘌呤碱基的DNA序列可以形成替代的二级结构，而不是像正常的两条DNA链的“扭曲阶梯”，而是一个非常紧密的四条DNA链的“立方体”。我们称这些结构为G-四链体。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，并已被证明在基因表达中发挥作用，并决定我们的细胞寿命。这些DNA序列在致癌基因中的发现比其他基因多，并且许多研究致力于设计靶向G-四链体结构的药物样化合物。尽管在知识上取得了这些进展，但尚未实现特异性靶向这些G-四链体结构。我们知道，非特异性但有效的化合物可以通过将它们与抗体连接而对某些类型的细胞更具特异性。抗体-药物缀合物是一类可用作靶向疗法以治疗诸如癌症的病症的生物药物。通过将药物样分子连接到抗体上，抗体将能够找到特定的患病细胞，而不去理会健康细胞。这使我们能够有一种药物，只针对需要治疗的细胞，例如癌症和健康细胞之间。重要的是，这种整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。我们以前的工作使我们了解了将药物与抗体连接起来的策略和战术。我们有初步的数据显示不同的方法来连接药物和抗体。我们将开发抗体药物偶联物，验证它们的特性和它们释放有效载荷的能力，只针对患病细胞。该项目的成果和潜在影响将促进我们对如何将药物连接到抗体的理解（并将适用于其他生物分子）。这项工作还将开发第一个抗体药物缀合物与G-四链体结合化合物作为有效载荷。结果将揭示一个新的抗体药物缀合物家族，以及将知识应用于其他系统的途径。

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.