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  Fragment-Based Lead Generation of Small Molecule Inhibitors of the Nsp3 Macrodomain in SARS-CoV-2


   Department of Chemistry

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  Prof P O'Brien  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Background: Coronaviruses (CoVs) are important human pathogens and SARS-CoV-2 is responsible for the current 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. [1]

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)

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. Development of lead-like Nsp3 macrodomain binders (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 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 used. 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.

Training: This project will provide state-of-the-art training in modern synthetic methodology and medicinal chemistry. It is an interdisciplinary project and there may 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] 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

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/training/idtc/idtctraining/

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/  

For more information about the project, click on the supervisor's name above to email the supervisor. For more information about the application process or funding, please click on email institution

This PhD will formally start on 1 October 2023. Induction activities may start a few days earlier.

To apply for this project, submit an online PhD in Chemistry application: https://www.york.ac.uk/study/postgraduate/courses/apply?course=DRPCHESCHE3

You should hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject. Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/


Chemistry (6)

Funding Notes

This project requires applicants to provide their own funding for tuition fees and living costs.
Tuition fees: https://www.york.ac.uk/study/postgraduate-research/fees/
Living costs: https://www.york.ac.uk/study/postgraduate-research/fees/living-costs/
You may like to apply for our Wild Prize or Wild Bursary to provide some additional financial support. You will need to have been made an offer of a place before being able to apply for these awards.
https://www.york.ac.uk/chemistry/postgraduate/research/funding/wild-prizes-and-bursaries/
You should hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject.
Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/

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