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

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.