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Developing Bio-orthogonal Ynamine Reagents for the Preparation of Next-Generation Antibody-Drug Conjugates


   Department of Pure and Applied Chemistry

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  Prof Glenn Burley, Dr Rebecca Beveridge, Dr Allan Watson  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Background

Biomolecule-based therapeutics – or biologics – have emerged as powerful modalities to treat diseases that are typically beyond the reach of conventional small molecules. However, to reach the full potential of biologics to deliver therapeutic payloads to the site of interest, synthetic methods are required to prepare these biologics (e.g., antibodies, therapeutic oligonucleotides). The current state-of-the-art in the preparation of antibody bioconjugates typically involve the formation of product mixtures where the site of functionalisation and the number of functional sites is not defined.

Previous work – Our collaborative team has recently identified the utility of aromatic ynamines as a superior reagent for the site-specific functionalisation of azides via a Cu-catalyzed alkyne-azide cycloaddition (CuAAC) reaction.[1-2] These alkyne surrogates require significantly less Cu catalyst are the only alkyne reagents reported to date which enable chemoselective control in a sequential two-step CuAAC process.[1,3]

Project Objective - The principal objective of this studentship is to develop aromatic ynamines as a powerful new bio-orthogonal reaction platform for the chemoselective tagging of antibodies and therapeutic oligonucleotides.

The specific aims of the project are to:

(i) gain a mechanistic understanding of the enhanced chemoselectivity of ynamines in CuAAC reactions, and potentially across other bio-orthogonal reaction classes.

(ii) establish conditions for chemoselective modification of antibodies and oligonucleotides.

(iii) prepare antibody-oligonucleotide conjugates and explore their biological activity in cell models.

Academic Environment - The student undertaking this project will receive unparalleled experience in all aspects of bioconjugate chemistry and chemical biology within the Strathclyde Centre for Molecular Bioscience (SCMB) – a new centre of excellence spanning chemistry and the biological sciences.  The Burley group (www.burleylabs.co.uk, University of Strathclyde) has extensive experience in small molecule synthesis, solid phase peptide/nucleic acid synthesis and the development of bioconjugation reagents.  In collaboration with the Watson group (University of St. Andrews, http://www.watsonresearchgroup.co.uk) we will explore the mechanistic aspects of these functional groups and apply this mechanistic insight to enhance their chemoselectivity. The analysis of these bioconjugates will also be explored using ion mobility mass spectrometry in collaboration with Dr Rebecca Beveridge.[4]


Funding Notes

This is an EPSRC Industrial CASE studentship in collaboration with GlaxoSmithKline (GSK). In addition to our Glasgow-based collaboration, the successful applicant will spend at least 3 months working alongside Chemical Biology groups at GSK’s Stevenage site.
This studentship is open to home and international students, and includes a stipend and fees for 4 years.
Candidates must have a strong background in Synthetic Organic or Medicinal/Biological Chemistry and have obtained a (i) or 2(i) [or equivalent for EU students] degree.

References

1. Hatit, M.Z.C.; Sadler, J.C.; McLean, L.A.; Whitehurst, B.C.; Seath, C.P.; Humphreys, L.D.; Young, R.J.; Watson, A.J.B.; Burley, G.A. "Chemoselective Sequential Click Ligations Directed by Enhanced Reactivity of an Aromatic Ynamine" Organic Letters, 2016, 18, 1694-1697.
2. Seath, C.P.; Burley, G.A. & Watson, A.J.B. "Determining the Origin of Rate-Independent Chemoselectivity in CuAAC Reactions: An Alkyne-Specific Shift in Rate-Determining Step" Angewandte Chemie International Edition, 2017, 56, 334-3318.
3. Hatit, M.Z.C.; Seath, C.P.; Watson, J.B.; Burley, G.A. "A Strategy for Conditional Orthogonal Sequential CuAAC Reactions Using a Protected Aromatic Ynamine" Journal of Organic Chemistry, 2017, 82, 5461-5468.
4. Beveridge, R.; Migas, L. G.; Payne, K. A.; Scrutton, N. S.; Leys, D.; Barran, P. E. “Mass spectrometry locates local and allosteric conformational changes that occur on cofactor binding” Nature Communications, 2016, 7, 1-9.
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