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

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

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.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S023755/1 01/04/2019 30/09/2027
2279379 Studentship EP/S023755/1 01/10/2019 30/09/2023 Ivan James Paul