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Exploring umpolung reactivity in the chemical synthesis of glycoproteins


   Department of Chemistry

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  Dr M A Fascione  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Background:

Although sugars, or glycans as they are commonly known, decorate every cell in the human body in the form of 'sweet' glycoproteins and play fundamental roles in humans, including mediating egg fertilization during reproduction and invasion of viruses during infection, as well as acting as potent vaccine therapeutics for infectious diseases, they are still poorly understood. This is primarily because the biosynthesis of glycoproteins is complex and can give rise to a number of different ‘glycoforms’ of a single protein. Such microheterogeneity has proven evolutionarily advantageous yet confounds studies into the bespoke activity and function of the individual glycoforms. The development of new scalable chemical methods to access such glycoproteins is therefore essential to study and harness their biological function in the design of ‘glycotherapeutics’. However current strategies for in vitro chemical synthesis of glycoproteins are hampered by a lack of precision and are often incompatible and unstable under biological conditions. In this PhD project we will build upon our previous work in this field (Chem. Sci. 20189 (25), 5585; ACS Chem. Biol., 2021, 16, (11), 2387) and address these limitations through the development of novel protein chemistry which enables flexible total chemical synthesis of glycoproteins by using carbene organocatalysis.

Objectives:

The goal of this project is to address limitations in the field by developing innovative ‘umpolung’ chemical bioconjugation methods using carbene organocatalysis to reverse the polarity of protein and small molecule aldehydes in the chemical synthesis of glycoconjugates. The novel platform technologies developed in this project will enable access to both unnatural glycoproteins and for the first time chemically derived native N-linked glycoproteins.

Specifically we will:

1)   Develop methods for the glyco-conjugation of proteins using carbene catalysts to reverse the polarity of aldehydes enabling access to unnatural glycoproteins.

2)   Develop the first chemical methods for the synthesis of native N-linked glycoproteins using a biomimetic approach which mimics how nature utilise carbene catalysts as enzyme co-factors in vivo.

3)   Deploy these methods in the synthesis of novel glycotherapeutics for treating urinary tract infections and Crohn’s disease.

Experimental approach:

This project transcends multiple disciplines, including, synthetic carbohydrate chemistry and catalysis, protein bioconjugation, and the mutation, expression and purification of proteins in E. coli. The project will specifically involve the chemical synthesis of small molecule glycan substrates and organocatalysts which will be deployed in the site-specific bioconjugation of proteins and will therefore require small molecule MS and NMR characterisation, and protein mass spectrometry using FT-ICR or LCMS.

Novelty:

Although sugars are the most abundant biomolecules on the planet, they are under-researched due to their complexity and dynamic function. This is particularly true for glycoproteins, where molecular level detail is severely lacking, and multivalent presentation to other biological actors is common and fundamentally important to life. The development of cutting edge chemical biology approaches to chemically build glycoproteins will therefore underpin and facilitate study in other fields of research such as biochemistry, human biology and materials chemistry. The project will also address fundamental unanswered questions in the field: Can we exploit the innate aldehyde functionality of glycans to attach them to proteins? Can we make stable C-C bonds to proteins by using umpolung carbene organocatalysts? And can we use these approaches to chemically construct native N-glycoconjugates which mimic the natural presentation of glycans on human and bacterial cells, providing access to novel glycotherapeutics?

Training:

The project will encompass and provide training in a wide variety of interdisciplinary ‘chemical biology’ techniques including synthetic carbohydrate chemistry and organocatalysis, small molecule characterisation, protein expression and purification and molecular biology, and protein characterisation e.g. SDS-PAGE and protein mass-spectrometry. 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/.

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.  Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/


Funding Notes

This studentship is fully funded for 3.5 years by an Engineering and Physical Sciences Research Council (EPSRC) Doctoral Training Partnership studentship and covers: (i) a tax-free annual stipend at the standard Research Council rate (£15,609 for 2021 entry), (ii) research costs, and (iii) tuition fees at the home or overseas rate.
Candidates of any nationality are welcome to apply and up to 30% of EPSRC DTP studentships may be awarded to exceptional international students.
See guidance for further details: https://www.york.ac.uk/chemistry/postgraduate/research/epsrc-stud/
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 (or equivalent https://www.york.ac.uk/study/international/your-country/) 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 remote panel interview on 30th or 31st March or 1st April 2022
• 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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