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Development of engineered reductive aminases (RedAms) for the regio- and enantioselective reductive amination of diamines with aldehydes


Project Description

Background – AstraZeneca has provided a set of real world targets for demonstration of the benefits of biocatalysis in synthetic strategies. These targets present excellent opportunities for the development of biocatalysts for both reductive amination (Reductive Aminases – RedAms) and amide bond formation (carboxylic acid reductases – CARs) both of which have been recently discovered at the University of Manchester. Reductive aminases have been shown to catalyse reductive amination between primary/secondary amines and ketones/aldehydes.1 In a proof-of-concept study, engineered CARs have recently been shown for the first time to catalyse amide bond formation between carboxylic acids and amines.2 Retrosynthetic analysis of the AZ drug candidates reveals two pathways for synthesis utilising CARs and RedAms.

Aims – The objective of this studentship is to develop a panel of engineered reductive aminases (RedAms) for applications in synthesis of AZ intermediates. New RedAm sequences will be identified, enzymes expressed in E. coli and activity characterised. The challenge within this project will be to identify RedAms that are regioselective with respect to diamines.4

Year 1 – Screening of our in house libraries of RedAms to identify enzymatic activity towards diamines.
Year 2 – Engineering of identified RedAms for enhanced activity towards aliphatic diamines.
Year 3 – development of gram scale biotransformations.
Year 4 – Development of enzymatic cascade coupling RedAms with CARs.

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) . 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. G. Aleku et al., Nat. Chem., 2017, 48, 1080
2. A. Wood et al., Angew. Chem. Int. Ed., 2017, 56, 14498;
3. D. Gahloth et al., Nat. Chem. Biol, 2017, 13, 975
4. G.-D. Roiban et al., ChemCatChem., 2017, 9, 4475

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