Development of dual catalysis systems for the preparation of peptide-drug conjugates

Antibody-drug or peptide-drug conjugates are three-component systems in which the protein, linker and payload must be optimised in order to achieve suitable targeting, uptake, release and pharmacological activity. We have been working on the development of peptide-drug conjugates that utilise the CCL2-CCR2 interaction to specifically target active compounds to a subset of immune cells known as monocytes. These conjugates have high activity/specificity and are active in cancer models, but the current preparation methods are not sufficiently scalable for us to develop them further.
The preparation of peptide-drug conjugates typically relies on the selective modification of natural amino acids, e.g. cysteine alkylation with maleimides, however these approaches suffer from poor specificity and cannot be easily applied in the CCL2-CCR2 system. As an alternative we have utilised CuAAC conjugation of unnatural amino acids, which allows very efficient and specific conjugation at the expense of flexibility and scalability of the protein component.
Chemoenzymatic conjugation methods (e.g. sortase, transglutaminase) allow the selective modification of specific amino acids or sequences with high efficiency under biocompatible conditions. While we have applied these methods to good effect in the preparation of novel peptide drug conjugates, these methods require synthesis of appropriately tagged linker-warhead combinations which limits the rate of optimisation of the linker-payload component.
In this project we aim to accelerate the synthesis of peptide-drug conjugates by combining the benefits of chemo- and bio-catalysis to prepare a range of conjugates from readily accessible modular building blocks. We will achieve this by:
1) Applying medicinal chemistry principles to the optimisation of amine donors for transglutaminase conjugation, thus reducing the equivalents of this component required to achieve selective conjugation.
2) Developing dual chemoenzymatic/CuAAC linker systems and applying these in the synthesis of novel peptide drug conjugates by dual catalysis.
3) Examining novel chemical catalysis systems to broaden scope beyond alkyne/azide chemistry.
As described above, the project seeks to develop synergistic chemo/bio-catalysis approaches to directly address challenges in the synthesis of complex protein systems, typified by peptide-drug conjugates.
The proposed project aims to develop new approaches to the synthesis of peptide/antibody-drug conjugates, with the potential to have a direct impact on the pharmaceutical industry and, ultimately, patient care. The development of new bioconjugation methods will also have implications for the broader field of Chemical Biology.
The discovery and development of complex medicines by the pharmaceutical industry contributes to human wellbeing globally and to UK economy directly through both exports and employment. New modalities (beyond small molecules and conventional mAb biologics) are of increasing importance in this arena, with several oligonucleotide and antibody-drug conjugate drugs approved in recent years.
The discovery of antibody-drug conjugates remains a key focus of many pharmaceutical companies, including for example AstraZeneca/Spirogen, Bicycle Therapeutics and LifeArc in the UK. The need for improved synthetic approaches to such compounds is evidenced by, for example, the recent investment in the UoM/AZ/ Prozomix Centre for Biocatalytic Manufacture of New Modalities (CBNM).
In addition to this the project will provide the student with relevant training in 1) chemical synthesis/purification/characterisation, 2) catalytic protein conjugation methodologies, 3) isolation and characterisation of labelled proteins and 4) application of peptide-drug conjugates in biological systems.

iCAT will work with industry partners to create an holistic approach to the training of students in biocatalysis, chemocatalysis, and their process integration. Traditional graduate training typically focuses on one aspect of catalysis and this approach can severely restrict innovation and impact. Advances in technology and fundamental reaction discovery are rendering this silo-approach obsolete, and a new training modality is needed to produce the next generation of chemists and engineers who can operate across a far broader chemical continuum. iCAT will meet this challenge with a state-of-the-art CDT, equipping the next generation of scientists and engineers with the skills needed to develop future catalytic processes and create the functional molecules of tomorrow.

The UK has one of the world's top-performing chemical industries, achieving outstanding levels of growth, exports, productivity and international investment. The UK's chemical industry is a significant provider of jobs and creator of wealth, with a turnover in excess of £50 billion and a contribution of over £15 Billion of value to the UK economy [2015 figures]. iCAT will deliver highly skilled people to lead this industry across its various sectors, achieving impact through the following actions:

1. Equip the next generation of science and engineering leaders with the interdisciplinary skills and knowledge needed to work across the bio and chemo catalytic remit and build the functional molecules we need to structure society.

2. Provide a highly skilled workforce and research base, skilled in the latest methodologies, strategies and techniques of catalysis and engineering that is crucial for the UK's Chemical Industry.

3. Build the critical mass necessary to support effective cohort-based training in a world-class research environment.

4. Develop and disseminate new catalytic technologies and processes that will be taken up by industrial and academic teams around the world.

5. Encourage Industry to promote research challenges within the CDT that are of core relevance to their business.

6. Provide cohesion in the integration of biocatalysis, engineering and chemocatalysis to create a more unified voice for strategic dialogue with industry, funders and policy makers, and more generally outreach and public engagement.

7. Draw-in and bring together Industrial partners to facilitate future Industrial collaborations.

8. Benefit Industrial scientists through interactions with the CDT (e.g. training and supervisory experience, exposure to cutting-edge synthesis and catalysis etc).

9. Link with other activities in the landscape: bringing unique expertise in catalysis to, for example, externally-funded University-led initiatives, EPRSC Grand Challenge Networks, and the National Catalysis Hub.