Development of new ligation systems for the preparation of peptide-drug conjugates

the research questions the project is trying to address/the objectives of the project

Antibody-drug or peptide-drug conjugates (ADCs) are three-component therapeutics frequently used in oncology medicine which consist of a protein recognition motif, a linker, and a payload - typically a cytotoxic drug. Optimisation of each component to achieve biological activity is a major research question and requires design and analysis of targeting, uptake, release and pharmacological activities.
This research project aims to 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 rely on use of synthetic proteins that are not sufficiently scalable for us to develop them further. The Butterworth group (University of Manchester) have developed peptide-drug conjugates that utilise a specific cytokine-receptor interaction to specifically target active compounds, and the Greaney group (University of Manchester) have developed metal-free ligation chemistry on simple small molecule systems that demonstrate exciting chemoselectivity and compatibility with aqueous conditions. This PhD project sets out an ambitious plan to unite the two approaches and define a new toolset for the construction of potent, selective ADCs on scale, and is supported by the biotechnology company LifeArc. ADCs are at the forefront of pharmaceutical industry research and are a key focus of many pharmaceutical companies in the UK.

the approach that will be taken to answer these questions (what the student will actually be doing)

We will develop two approaches to realise the synthesis of novel peptide-drug conjugates:

1) Apply medicinal chemistry principles to the optimisation of amine donors for transglutaminase (an enzyme that facilitates conjugation), thus reducing the equivalents of this component required to achieve selective conjugation. Chemoenzymatic conjugation methods can proceed with high efficiency under biocompatible conditions, but typically require laborious syntheses of appropriately tagged linker-warhead combinations, limiting optimisation of the linker-payload component.

2) Examine novel ligation chemistries to broaden scope beyond alkyne/azide chemistry. The Smiles arylation chemistry developed in the Greaney lab works in water, and is efficient and reliable. Further, the components of the reaction are very bio-compatible, with sulfonamides being mainstays of medicinal chemistry prized for their metabolic stability, and alkynes being the archetypal click component having proven application in numerous chemical biology studies. The chemistry has the powerful feature of generating a fluorescent linkage, creating a functional readout for successful ligation and tracking of cellular uptake and distribution.

the novel engineering and/or physical sciences content of the research (the science that places it within EPSRC's remit).

The studentship will create an ambitious, cross-disciplinary research environment which sits within both the EPSRC remits of physical sciences and healthcare technologies, addressing the following areas: Catalysis, Chemical biology and biological chemistry, and synthetic chemistry.