Towards New Antivirals for the Treatment of COVID-19: Fragment-Based Lead Generation of Small Molecule Inhibitors of the Nsp3 Macrodomain in SARS-CoV-2

Background:

Coronaviruses (CoVs) are important human pathogens and SARS-CoV-2 is responsible for the COVID-19 pandemic. Notwithstanding progress in available vaccines for COVID-19, there remains a need to develop small molecule drug candidates for treating COVID-19.

Objectives:

Based on preliminary findings, this PhD studentship will focus on the use of fragment-based lead generation[1] to discover small molecule inhibitors of the Nsp3 macrodomain, a novel enzyme target in SARS-CoV-2. Ultimately, the results could underpin the development of a new treatment of COVID-19 (and future CoV-related diseases).

1. Design, synthesis and analysis of Nsp3 macrodomain binders with IC50 <5 M activity (Years 1-3)
2. Mapping out structure-activity relationships for the macrodomain (Years 2-3)
3. Preliminary exploration of translation potential (metabolic stability) (Years 2.5-onwards)

Collaborators:

Ivan Ahel (Sir William Dunn School of Pathology, University of Oxford) and Frank von Delft (Diamond Light Source, XChem screening facility and Centre for Medicines Discovery, University of Oxford)

Experimental Approach:

In a collaborative project, the interdisciplinary team (molecular biology, synthetic and medicinal chemistry, biophysics, X-ray crystallography) have obtained preliminary fragment hits (234 structures) from an X-ray crystallographic screen of the Nsp3 macrodomain, some of which have been validated in an in vitro biochemical assay (HTRF-based ADPr-peptide displacement).[2,3] To progress to lead compounds, iterative rounds of “design, test, make” will be carried out by the PhD student. The design (structure-based, computational docking) and synthesis parts will be carried out in the O’Brien group at York, with the Ahel and von Delft groups providing read-outs of activity and binding via the biochemical assay and X-ray crystallography respectively. This medicinal chemistry project will provide wide-ranging training for the PhD student.

Training:

Experience of synthetic organic chemistry is required. This project will provide state-of-the-art training in modern synthetic methodology and medicinal chemistry. It is an interdisciplinary project and there will be opportunity to spend short placements in the groups of Ivan Ahel and Frank von Delft. The graduating PhD student will be fully equipped for a future career in the pharmaceutical industry.

The York Biomedical Research Institute at the University of York is committed to recruiting extraordinary future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation, religion/belief, marital status, pregnancy and maternity, or career pathway to date. We understand that commitment and excellence can be shown in many ways and have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.