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Conjugate-addition/ring-expansion cascade reactions: chemical ratchets for the site selective modification of lysine residues in proteins


   Department of Chemistry

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  Dr W Unsworth, Dr M A Fascione, Dr C Spicer  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

Background:

Chemically modified proteins are invaluable tools, allowing researchers to study cell and tissue biology, develop treatments for disease, and address global challenges in sustainability through bio-catalysis. However, achieving site-selective modification remains a major challenge. In this project, we propose to exploit novel ring expansion cascade reactions developed in the Unsworth lab [e.g. Angew. Chem. Int. Ed. 2015, 54, 15794 –15798; Angew. Chem., Int. Ed. 2019, 58, 13942–13947; Chem. Eur. J. 2020, 26, 12674–12683] to enable the selective chemical modification proteins. More specifically, reactions based on conjugate-addition/ring-expansion (CARE) cascade reactions between cyclic imides and amines will enable lysine residues on peptides and proteins to be functionalised highly selectively. Many nucleophilic groups in proteins (e.g. amines, thiols, alcohols etc.) are known to take part in conjugate addition reactions with Michael acceptors, but poor selectivity and/or reversibility in this step limit its value for selective protein modification. A key design feature of this project is the ring expansion that follows conjugate addition – crucially, ring expansion can only take place when the nucleophile is a primary amine, which effectively serves as a chemical ‘ratchet’ to lock the newly added function group in place.

Objectives:

1) To verify that CARE reactions are compatible with model synthetic peptides containing a lysine residue.

2) To extend this idea to more proteins.

3) To design a series of imide units with complementary reactivity/selectivity to expand the scope of the method.

4) To design imide units functionalised with fluorescent- and affinity-biological reporters

5) To apply the developed technology to the synthesis of cyclic-adhesive peptides able to mediate cell attachment to materials.

Experimental Approach:

This inter-disciplinary project requires a mix of synthetic organic chemistry (Unsworth), peptide chemistry (Spicer) and chemical biology (Fascione). Synthetic aspects will be conducted in the Unsworth group and include the synthesis of imides, preparation of test systems, ring expansion reactions and mechanistic studies. Peptide work, led by Spicer, will include the synthesis of a panel of substrates containing different amino acid functionalities, and analysis of their modification. Chemical biology aspects in the Fascione lab will include mutation, expression and purification of candidate proteins in E. coli, bioconjugation of proteins with small molecules and their characterisation by protein mass spectrometry (FT-ICR or LCMS).

Novelty:

If realised, this would represent a completely novel approach for peptide and protein modification; to the best of our knowledge, there are no reports of ring expansion reactions being used for protein functionalisation.

 Training:

The appointed student will acquire a valuable mixed skill set spanning synthetic organic chemistry and biological chemistry. Training in synthetic organic chemistry will be provided to ensure the student has a strong overall knowledge of organic chemistry and associated practical techniques. This will be supplemented by attendance at the organic problem classes. The student will also be trained in spectroscopy, especially NMR characterisation of complex compounds, and mass spectrometry. Through their work with the Spicer and Fascione Groups, the student be trained in solid-phase peptide synthesis, recombinant protein expression, bioconjugation, and other chemical biology techniques. Group meetings will allow regular opportunities to develop skills in presenting and discussing scientific ideas. The student will also be encouraged to attend courses provided by the iDTC and the researcher development unit in York. The student’s transferable skills will be enhanced by attendance at courses on science communication, thesis writing, time management, and presentation 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/.

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 2022. 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.  


Funding Notes

Fully funded for 3 years by the Department of Chemistry and covers: (i) a tax-free annual stipend at the standard Research Council rate (£15,609 for 2021-22), (ii) tuition fees at the Home rate, (iii) funding for consumables. See guidance for further details: https://www.york.ac.uk/chemistry/postgraduate/research/dept-stud/
Studentships are available to any student who is eligible to pay tuition fees at the home rate: https://www.york.ac.uk/study/postgraduate-research/fees/status/
Not all projects will be funded; candidates will be appointed via a competitive process.

References

Candidate selection process:
• You should hold or expect to receive at least an upper second class degree in chemistry or a chemical sciences related subject
• Applicants should submit a PhD application to the University of York by 28 February 2022
• Supervisors may contact candidates either by email, telephone or web-chat
• Supervisors can nominate up to 2 candidates to be interviewed for the project
• The interview panel will shortlist candidates for interview from all those nominated
• Shortlisted candidates will be invited to a panel interview on 30th or 31st March or 1stApril
• The awarding committee will award studentships following the panel interviews
• Candidates will be notified of the outcome of the panel’s decision by email

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