Centre for Biocatalytic Manufacture of New Modalities (CBNM)

Lead Research Organisation: University of Manchester
Department Name: Chemistry


In the ever developing world of pharmaceuticals and treatments of diseases new, more challenging drug targets are being identified that require ever more complex drug molecules. These complex molecules or "New Modalities" bridge the gap between the two existing classes of compounds, small molecules (e.g. Aspirin) and biologics (Antibodies), and are typically larger than the existing small molecules but smaller than traditional biologics. These new classes of molecule offer great promise as novel therapies and indeed many of these medicines are aimed at biological targets that cannot be addressed by traditional either small molecule or antibody derived drugs.

The complexity of the new modalities currently results in high cost of manufacture which offers an opportunity to develop lower cost routes to produce these compounds. Small molecule manufacturer has benefited from adopting biocatalysis within manufacturing strategies and has demonstrated the potential for use of these catalysts in wider chemical manufacture, such as reduced waste streams, lower energy costs and reduced costs of goods including solvents. Indeed, the project partners have already generated some early proof-of-concept studies, backed up by a wider literature evidence base suggesting that biocatalysis can be used in the synthesis of these new modalities.

Through the partnership of the University of Manchester, AstraZeneca and Prozomix we are bringing together a diverse range of experts that will facilitate the development of new manufacturing strategies to produce these new modalities in an efficient and cleaner manner. The use of biocatalysis has the potential to allow access to chemistries and control of manufacture that are otherwise unavailable to the pharmaceutical manufacturing community. Culminating in lower cost manufacturing that translates into greater access to the next generation of drug for a wider community.

Planned Impact

The Centre address a clear challenge facing the pharmaceutical manufacturing community. The efficient and economic production of New Modalities poses a significant problem due to their relative complexity, compared to traditional small molecules, as they possess multiple stereogenic centres and a myriad of functional groups that would otherwise require protection and de-protection steps to ensure correct transformations. Additionally, maintaining stereo- and regio-selectivity during the synthesis of complex molecules is critical to their efficacy and safety when administered to patients. Biocatalysts have demonstrated their ability to add value to small molecule manufacturing by allowing strict control over the incorporation/interconversion of functional groups. Through design of the manufacturing processes from the bottom up, incorporating biocatalysis from the outset we aim to develop bespoke manufacturing technologies for a range of real world drug targets within the AZ product portfolio.

The societal and economic impacts from this research programme will be realised through the development of biocatalysis & biotransformation capabilities to underpin sustainable chemicals manufacturing processes. The proposed activities will open up cost effective routes to a range of new modality drug targets. Our activities also will underpin sustainable manufacture across many areas, including bulk and fine chemicals, and API synthesis for pharmaceuticals manufacture and new catalysts will find widespread application in more traditional manufacturing processes e.g. food processing, tanning, paper manufacture and related industries.

The Centre draws together expertise from across disciplines enabling experts to work together and interact effectively. This will provide cohesion to integrate the disciplines of biocatalysis, engineering and chemistry and train a new generation of catalysis scientists who will work effectively across the chemicals synthesis, theoretical modelling, process development and bioscience disciplines. Embedding Industry in to the partnership will ensure that the processes developed maintain focus and provide a direct route to exploitation of the academic research.

The global renewable chemicals market is expected to grow from $51.7 billion in 2015 to $85.6 billion by 2020, with a compound annual growth rate of 10.6% for this period. Due to the critical demand for eco-friendly routes to chemicals and materials the use of enzymes and renewable technologies is set to explode over the next decade. In the UK alone, synthetic biology research has received £300M of public sector investment over the last eight years. This project will develop multiple technologies which can be adopted by wider industry and service providers. Increasing the overall sustainability and competitive edge of several biotechnology applications will be of huge benefit to the pharmaceutical and fine chemicals industries.

Alignment and collaboration with existing centres such as MDC and NoWCADD will create a pipeline from biomarker discovery through to manufacture of drug targets. This will increase the impact of not only CBNM but potentially the other centres also.


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Barker RD (2022) Mechanism of Action of Flavin-Dependent Halogenases. in ACS catalysis

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Heath RS (2022) An Engineered Cholesterol Oxidase Catalyses Enantioselective Oxidation of Non-steroidal Secondary Alcohols. in Chembiochem : a European journal of chemical biology

Description We are taking forward the current developments on Antisense Oligonucleotide development into a wider consortium. Prof Turner was awarded the Nucleic Acid Therapeutics Accelerator Manufacturing grant by the MRC. This consortium involves all the CBNM project partners but brings in additional companies such as Agilent Technologies and Nuclera Nucleics, the NATA Hub based at Harwell, LGC Ltd, Amgen and EUROAPI. The proof of concept work performed within the CBNM provided the confidence in the biocatalytic approach that is now being championed by this wider consortium. Both projects will work alongside each other to ensure the development of complementary objectives through shared best practice.

We have developed a glycoengineering technology to synthesize antibody-drug conjugates (ADCs) with antibody-to-drug ratio (DAR) of up to 8 using Trastuzumab in its native form as a model antibody. Fundamental to our methodology is the generation of four aldehyde biorthogonal handles using the biocatalyst galactose oxidase (GOase), which is remarkably selective toward D-galactose units of the antibody remodelled N-glycan. Subsequent aldehydes functionalization via tandem Knoevenagel-Michael addition (TKM) allows to switch from moderate- to high-drug loading ADCs, that is from maximum DAR of 4 to 8.

We have developed the application of adenylation domains of carboxylic acid reductases as standalone biocatalysts towards biocatalytic amidations. We found that coenzyme A and structurally related derivatives couple efficiently to carboxylic acids catalysed by the CAR A-domain, the benefit of this is the use of equimolar or even catalytic quantities of thiol relative to carboxylic acid. Combination with CoA-dependent acyltransferases established a modular cascade allowing in-situ regeneration of acyl-CoA derivatives to gain access to non-natural acyl-CoA thioesters. Using this approach synthesis of a broad variety of pharmaceutically relevant amides that are important for R&D at AstraZeneca could be made accessible. In particular, by combination with different N-acyltransferases, functionalised aryl- and benzylamines can be coupled with a variety of carboxylic acids to make amides.
Exploitation Route New biocatalytic manufacturing platforms can be used by others and adapted for their own specific chemical targets.
Sectors Chemicals,Manufacturing, including Industrial Biotechology

Description Disyn Biotec provides expertise in biocatalyst development and will work closely with our partners to support sustainable manufacturing. Through implementation of our RetroBiocat platform for faster and efficient synthetic route design, we will drive the next revolution in industrial biotechnology. 
Year Established 2021 
Impact Disyn Biotec is currently taking forward the RetroBioCat platform that was developed within the Turner Lab.
Website https://disynbiotec.com/