Details of Grant 

EPSRC Reference:	EP/T01430X/1
Title:	Catalytic Synthesis of Pharmaceutical Amides in Water
Principal Investigator:	Grogan, Professor GJ
Other Investigators:	Fairlamb, Professor IJ
Researcher Co-Investigators:
Project Partners:	GlaxoSmithKline plc (GSK) University of Freiburg
Department:	Chemistry
Organisation:	University of York
Scheme:	Standard Research
Starts:	01 October 2020	Ends:	31 March 2024	Value (£):	442,674
EPSRC Research Topic Classifications:	Catalysis & Applied Catalysis
EPSRC Industrial Sector Classifications:	Chemicals Pharmaceuticals and Biotechnology
Related Grants:
Panel History:	Panel Date Panel Name Outcome 05 Dec 2019 EPSRC Physical Sciences - December 2019 Announced
Summary on Grant Application Form
The amide bond is arguably the most significant in pharmaceutical chemistry, featuring in a host of important everyday pharmaceuticals for the treatment of ulcers, high cholesterol and pathogenic infections by bacteria and viruses. It is vital therefore that there exist atom efficient and sustainable green chemical methods for the synthesis of pharmaceutical amides. However, industrial synthetic methods for the preparation of amides suffer from the use of complex or hazardous reagents to accomplish their chemistry and generate a large amount of waste. Because of this lack of efficiency, industrial synthetic chemists are increasingly turning towards 'biocatalysis' or 'Industrial Biotechnology' as the preferred method of synthesising molecules for pharmaceutical production. Biocatalysts, such as enzyme or microbes, typically achieve the synthesis of chemical bonds with excellent atom efficiency and selectivity, and Nature is also expert at synthesising amide bonds, which are the major bonds that hold the structure of proteins together. Until now however, biocatalysts for the formation of amide bonds have received little attention for industrial application, even though such enzyme reactions feature at the top of the list for many chemists looking for biocatalytic solutions to synthetic problems. This is because biocatalytic methods for amide bond formation in Nature, while efficient, are often complex, and difficult to apply out of their natural context. A recently discovered group of enzymes, which we have called amide bond synthetases (ABSs), offers new and unexplored promise for biocatalytic amide bond formation, as their reaction chemistry is comparatively simple, and also because the kind of amide bonds that they form, are much more closely related to molecules of real pharmaceutical interest than has previously been the case. In this project, which is a collaboration between biochemists and synthetic chemists at York, and in association with GSK and also the University of Freiburg, we propose to thoroughly investigate the synthetic potential of the new ABS enzymes. First we will define the potential and limitations of the natural enzymes using a mixture of synthetic chemistry and biocatalysis. We will then use the recently-determined structure of the ABS enzyme McbA to engineer the enzyme, expanding its potential for the catalysis of the synthesis of a much wider range of pharmaceutically relevant molecules. We will also use contemporary protein evolution techniques to adapt the enzymes to act on alternative substrates that are of interest to industrial collaborators. We will also apply new techniques in enzyme cofactor recycling to allow us to scale up the amide bond forming reactions, and also immobilise the enzymes in order to establish a flow biocatalysis system for amide synthesis. Finally, we will combine ABSs with other enzymes to create 'cascades' for the synthesis of amides from readily available alcohol and amine substrates. Together, the project will establish a new frontier in biocatalytic amide bond formation with a view to more sustainable chemical processes for the industrial synthesis of pharmaceuticals.
Key Findings
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Organisation Website:	http://www.york.ac.uk