Engineering inducible anhydrides for irreversible Red Blood Cell enzyme decoration

许多治疗药物在几小时内就会从体内清除，因此人们需要定期服用药物以保持疗效。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时间更长。红细胞也是重要的治疗载体，因为它们在身体的所有血管中移动，与一些最重要的疾病有关，如心脏病发作、中风和癌症的生长。我们的团队之前在体外制造红细胞方面取得了进展。我们还能够从红细胞中去除许多血型标记，以获得更多用于输血的通用细胞。将蛋白质药物结合到红细胞表面的传统方法是通过常规的蛋白质相互作用，如抗体，抗体可以在几个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在特定细胞表面蛋白质上并形成不可逆键的方法。这个反应是快速的，由钙激活，为细胞偶联提供了温和的条件。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，效率和一般适用性。然后，我们将优化与代谢疾病或溶解凝块相关的酶对红细胞的不可逆修饰。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潜力，成为一种经济有效且持久的治疗方法。

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.