###The design, synthesis and evaluation of fragment-based small chemical probes of the SARS-CoV-2 non-structural protein 1
Project ID: 2228bd1124 (You will need this ID for your application)
Research Theme: Healthcare Technologies
UCL Lead department: School of Pharmacy
Lead Supervisor: Geoff Wells
Project Summary:
The aim of this project is to develop small molecule inhibitors of the SARS-CoV-2 non-structural protein-1 (nsp1). The pandemic caused by the SARS-CoV-2 coronavirus continues to impact on societies across the world, particularly sub-populations with pre-existing health conditions and/or low vaccine coverage. The world also needs to prepare for future outbreaks of mutant forms of the SARS-CoV-2 virus and other, related coronaviruses. This project focusses on nsp1 that plays a role in the pathogenicity (infectiveness) of the virus and helps to suppress the normal protein production within human cells. It achieves this by binding to the 40s ribosome and inhibiting its activity, although there is much still to be learned about nsp1 structure (e.g. the disordered C-terminal region) and function. In the project you will design compounds for synthesis based on nsp1 fragment ligands identified by the supervisory team using high-throughput x-ray crystallography methods (https://doi.org/10.7554/eLife.81167) and apply computational ligand design methods. You will synthesise and characterise the selected compounds, then we will use a combination of x-ray crystallography, and ligand binding assays to test nsp1 inhibition. We will repeat this design-make-test-analyse cycle to make high affinity inhibitors of nsp1. Following this we will provide the best compounds to collaborators to determine their effects on the virus life cycle, and their potential to both enhance our mechanistic understanding of how nsp1 functions in human cells and act as leads for future drug development. We are looking for a student with a strong background in chemistry, or biological/medicinal chemistry that is keen to work in a multidisciplinary environment and willing to learn new skills in chemical biology, fragment-based ligand design and early-stage drug discovery. Training in the research methods will be complemented by the PhD student training program in the School of Pharmacy, chemistry problem solving tutorials and regular group meetings.