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Selective bio-conjugation of chemical probes to new modalities using acylases as biocatalysts

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  • Full or part time
    Prof S Flitsch
    Prof P Barran
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Background – A key challenge in the production of bioconjugates is linker chemistry, which needs to fulfil a number of criteria to be useful for industrial applications:
(i) the degree of ‘tagging’ required for conjugation should be minimised
(ii) conjugation chemistry should be applicable to a broad range of complex molecular entities including small molecules, proteins and nucleic acids
(iii) conjugation efficiency should be high and selective
(iv) good control over valency of conjugation with scope for valencies from 1 to over 10
(v) control of positioning of label on large biomolecules such as proteins
(vi) conjugation should not interfere with biological activity and should be stable during delivery
(vii) flexibility of using cleavable and non-cleavable linkers

The majority of current conjugation methods make use of highly selective cysteine-targeted alkylation chemistries, such as addition of cysteine thiols to maleimides, taking advantage of natural or engineered cysteine residues in proteins. This thiol-based methodology has several disadvantages (need for mutagenesis, reversibility/instability of linker) and new bioconjugation strategies are now a topic of many investigations. Enzymatically mediated conjugations are particularly attractive, because of their biocompatibility, selectivity and efficiency and a number of methods have been developed.

Aims – In this project we shall explore an alternative strategy, instead of conjugation at cysteine residues we will target lysine residues using direct enzyme acylation strategies. Potential candidates for acylation enzymes are penicillin acylase and homologues (which has very broad substrate spectra for the amine component of the acylation reaction and have been reported act of proteins). More recently, we have shown that carboxylic acid reductase can be used for acylation chemistries.1 The targeting of specific lysines by different acylases and their homologues will be systematically explored using a panel of homologues produced by the industrial project partner Prozomix and analysis through advanced mass spectrometry techniques.

Year 1 – Synthesis of different linker types, work alongside PhD project 2 to develop appropriate analytical techniques
Year 2 – identify and screen potential penicillin acylase homologues
Year 3 – engineering of candidate acylase enzymes for improved activity towards selected linker(s)
Year 4 – Development of biotransformations to demonstrate biocatalytic route.

We welcome applications from graduates with a good UK honours undergraduate degree (1st class or a high 2i), or a first degree with an additional masters degree or international equivalent, in chemistry, biochemistry, biology or another aligned science subject. Applicants should be looking for a challenging, interdisciplinary research training environment.

All applicants should send their CV and covering letter to Dr Ian Rowles (CBNM Project Manager) [Email Address Removed]. Applications will be reviewed as they are received until a candidate is selected; therefore candidates are encouraged to apply early.

Funding Notes

This is a 4 year studentship jointly funded by the EPSRC, AstraZenca and the University of Manchester, covering all fees and stipend (£14.777 in September 2018). Open to UK/EU applicants only.

The start date for this PhD prgramme will be September 2019.

References

1. A.L.H. Wood et al., Angew. Chem. Int. Ed., 2017, 56, 14498



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