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


   York Biomedical Research Institute


About the Project

Applications accepted for PhD Only

Background: Coronaviruses (CoVs) are important human pathogens and SARS-CoV-2 is responsible for the current COVID-19 pandemic (>260m cases, 5.2m deaths). 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, the interdisciplinary team (molecular biology, synthetic and medicinal chemistry, biophysics, X-ray crystallography) will use fragment-based lead generation[1] to discover small molecule inhibitors of the Nsp3 macrodomain, a novel enzyme target that is present in SARS-CoV-2. Ultimately, the results could underpin the development of a new treatment for 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 (cell permeability, metabolic stability) (Years 2.5-onwards)

Experimental Approach: In a recently initiated collaboration between the O’Brien, Ahel and von Delft research groups, 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. 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.

Training: 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.

References

[1] D. A. Erlanson, S. W. Fesik, R. E. Hubbard, W. Jahnke and H. Jhoti, Nat Rev Drug Discov, 2016, 15, 605

[2] M. Schuller et al., Sci. Adv., 2021, 7, eabf8711

[3] https://www.diamond.ac.uk/covid-19/for-scientists/NSP3-macrodomain-structure-and-XChem.html

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 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.

Entry Requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions. 

Programme: PhD in Biomedical Science (3 years)

Start Date: 1st October 2022

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Funding Notes

This is a self funded research project. Applicants need to have adequate funds to meet the costs of a self-funded research project including tuition fees and living expenses for the duration of the research programme.

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