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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


   Department of Chemistry

   Applications accepted all year round  Self-Funded PhD Students Only

About the 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

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)

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 – Pfizer is currently commercialising a small molecule that targets the 3CL protease (MPro) of SARS-CoV-2.[1]

Objectives: Based on preliminary findings, the interdisciplinary team (molecular biology, synthetic and medicinal chemistry, biophysics, X-ray crystallography) will use fragment-based lead generation[2] 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)

The COVID-19 pandemic has presented numerous unexpected opportunities for impact in the development of new treatments, based on fundamental interdisciplinary scientific research. This project is clearly timely given the current ongoing word-wide situation.

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).[3,4] 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. Initial synthetic efforts will be focused on progressing the O’Brien group fragment hits. For this, methodology that is already established in the group will be deployed. Then, different series of elaborated fragments will be designed and new synthetic routes and methodology will be developed as required. In particular, there will be scope to utilise the O’Brien group’s new strategy for fragment elaboration in 3-D (using designer 3-D building blocks). This synthetic medicinal chemistry project will provide wide-ranging training for the PhD student.

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. Well-behaved inhibitors for this domain have not been developed to date.

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.

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/cdts/

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/ .


Funding Notes

This project is open to students who can fund their own studies or who have been awarded a scholarship separate from this project. The Chemistry Department at York is pleased to offer Wild Fund Scholarships to new students who will pay tuition fees at the overseas rate. Scholarships are competitive and awarded based on academic ability and financial need. For further information see: View Website

References

References
[1] https://www.science.org/doi/10.1126/science.abl4784
[2] D. A. Erlanson, S. W. Fesik, R. E. Hubbard, W. Jahnke and H. Jhoti, Nat Rev Drug Discov, 2016, 15, 605
[3] M. Schuller et al., Sci. Adv., 2021, 7, eabf8711
[4] https://www.diamond.ac.uk/covid-19/for-scientists/NSP3-macrodomain-structure-and-XChem.html

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