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 - Pfizer have developed Paxlovid, a small molecule that targets the 3CL protease (MPro) of SARS-CoV-2.
Objectives: Based on preliminary findings, this PhD studentship, working within an interdisciplinary team (synthetic and medicinal chemistry, molecular biology, biophysics, X-ray crystallography), 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 μM 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 3-3.5)
Novelty: The macrodomain is a 150 amino acid protein module with (ADP-ribosyl)-hydrolase activity that is a part of the SARS-CoV-2 multidomain protein Nsp3. ADP-ribosylation is a reversible post-translational modification of proteins synthesised by the PARP family of enzymes, and regulates many pathways in human cells, including antiviral defences. Several of the human PARPs (e.g. PARP14) act as antiviral proteins to prevent virus replication. In contrast, the viral macrodomain removes the ADP-ribosylation modifications, thereby enabling the virus to counteract the PARP-induced innate immunity. Thus, the macrodomain enzyme represents a promising and novel drug target for the treatment of coronavirus infections.
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.
Main supervisor: Peter O’Brien (University of York)
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)
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog
Further information on the programme and how to apply can be found on our website:
https://www.dimen.org.uk/how-to-apply
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