Engineering inducible anhydrides for irreversible Red Blood Cell enzyme decoration

工程诱导酸酐用于不可逆红细胞酶修饰

• 批准号: EP/W01565X/1
• 负责人: Mark Howarth
• 金额: $ 108.06万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FW01565X%2F1
• 关键词: Engineering; inducible; anhydrides; irreversible; Red

Many therapeutics drugs are cleared from the body in a matter of hours, so that people need to take the drug regularly to maintain the benefit. Red blood cells circulate around the bloodstream for 4 months. Therefore, binding to a red blood cell could allow drugs to be effective for much longer. Red blood cells are also important therapeutic vehicles because they move through all the blood vessels of the body, being involved in some of the most important diseases, namely heart attack, stroke and cancer growth. Our team has previously made advances enabling the production of red blood cells outside the body. We have also been able to remove many blood group markers from red blood cells, towards more universal cells for blood transfusion. The conventional way to bind protein drugs on the surface of red blood cells is through regular protein interactions like antibodies, which can fall off the red blood cell in hours. Through harnessing bacterial protein chemistry, we have identified a way to attach to specific cell-surface proteins and form an irreversible bond. This reaction is rapid and activated by calcium, providing gentle conditions for coupling to cells. Here we will use structure-based design and evolution to increase the speed, efficiency and general applicability of this irreversible protein reaction. We will then optimise the irreversible decoration of red blood cells with enzymes related to metabolic diseases or dissolving clots. Through this engineering of a new approach in protein chemistry, we can help red blood cells reach their potential as a cost-effective and long-lasting therapy.

许多治疗药物在几个小时内从体内清除，因此人们需要定期服用药物以保持益处。红细胞在血液中循环4个月。因此，与红细胞结合可以使药物有效更长时间。红细胞也是重要的治疗工具，因为它们穿过身体的所有血管，参与一些最重要的疾病，即心脏病发作，中风和癌症生长。我们的团队以前已经取得了进展，能够在体外生产红细胞。我们还能够从红细胞中去除许多血型标志物，以获得更通用的输血细胞。将蛋白质药物结合在红细胞表面的常规方法是通过常规的蛋白质相互作用，如抗体，抗体可以在几小时内从红细胞上脱落。通过利用细菌蛋白质化学，我们已经确定了一种附着于特定细胞表面蛋白质并形成不可逆键的方法。这种反应是快速的，并被钙激活，为偶联到细胞提供温和的条件。在这里，我们将使用基于结构的设计和进化来提高这种不可逆蛋白质反应的速度，效率和普遍适用性。然后，我们将用与代谢疾病或溶解凝块相关的酶优化红细胞的不可逆装饰。通过这种蛋白质化学新方法的工程设计，我们可以帮助红细胞发挥其作为一种具有成本效益和持久治疗的潜力。