Production of full-length proteins of the COVID encounter complex for structural analysis and drug discovery

生产新冠病毒复合物的全长蛋白质，用于结构分析和药物发现

• 批准号: BB/V018051/1
• 负责人: Timothy Dafforn
• 金额: $ 54.52万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV018051%2F1
• 关键词: Production; full; length; proteins; COVID

The virus SARS-CoV-2 has changed the lives of the world population. The virus is a member of the corona virus family that infects a range of cells in the body, the most important being those of the respiratory tract. The global importance of this disease has led to an extensive effort to develop new therapies that mitigate its effects. One route for developing such therapeutics is to find a way of blocking the entry of the virus into the cells of the host. This process is mediated by a protein on the surface of the virus (Spike) that docks with a protein on the surface of human cells (ACE2). This process is aided by other proteins on the cell surface including one called B0AT1. If this interaction between Spike and ACE2 could be blocked by a drug, then the infection could the inhibited. Unfortunately, all of these proteins a part of a membrane; either the membrane that surrounds the virus or the membrane that surrounds the cell. This makes it technically challenging to make these proteins meaning that is can be difficult to carry out the studies required to produce new drugs.At the Universities of Birmingham and Oxford we have developed 2 novel systems that allow us to make these proteins in a stable form. This enables us to study process of viral binding to human cells in unprecedented detail. In this project we will use these methods to produce each protein and then assemble them to form the structure that triggers viral infection of the cell. We will use Electron Microscopy to study this structure to identify regions that could be targeted by drugs. We will then use the same protein samples to develop systems that could be used to test a wide range of drugs that might inhibit the formation of this complex. Taken together, success in this project could lead to new therapies for SARS-CoV-2 and other corona viruses.

SARS-CoV-2病毒改变了世界人口的生活。该病毒是冠状病毒家族的一员，感染体内的一系列细胞，最重要的是呼吸道细胞。这种疾病的全球重要性导致了广泛的努力，以开发新的疗法，减轻其影响。开发这种疗法的一种途径是找到一种阻止病毒进入宿主细胞的方法。这一过程由病毒表面的一种蛋白质（刺突）介导，该蛋白质与人类细胞表面的一种蛋白质（ACE 2）对接。这一过程由细胞表面的其他蛋白质辅助，包括一种称为B 0AT 1的蛋白质。如果Spike和ACE 2之间的这种相互作用可以被药物阻断，那么感染就可以被抑制。不幸的是，所有这些蛋白质都是膜的一部分;要么是包围病毒的膜，要么是包围细胞的膜。这使得制造这些蛋白质在技术上具有挑战性，这意味着很难进行生产新药所需的研究。在伯明翰大学和牛津大学，我们开发了两种新系统，使我们能够以稳定的形式制造这些蛋白质。这使我们能够以前所未有的细节研究病毒与人类细胞结合的过程。在这个项目中，我们将使用这些方法来生产每种蛋白质，然后将它们组装成触发病毒感染细胞的结构。我们将使用电子显微镜来研究这种结构，以确定药物可能靶向的区域。然后，我们将使用相同的蛋白质样品开发系统，可用于测试可能抑制这种复合物形成的各种药物。总之，该项目的成功可能会导致SARS-CoV-2和其他冠状病毒的新疗法。