An Integrated Platform for Modular Manufacturing and Drug Discovery

Project Overview:

The first of the GSK-EML projects aims to discover and develop new polymers as therapeutic agents, and to simultaneously create novel manufacturing routes for producing these new polymers.  It has a particular emphasis on the inherent scalability and modularity of polymer synthesis from discovery through to clinical applications and manufacturing.

The manufacturing focus of the project to date has been on the synthesis of oligonucleotide therapeutics. This manufacturing platform relies upon standard pharmaceutical industry equipment and offers attractive advantages for scale-up compared to solid-phase synthesis.  It can also be used to synthesise synthetic polymers such as PEG, and beyond this many more complex biopolymers of great therapeutic potential as they are identified.

Of particular interest in this project is an important type of chemical modification known as ADP-ribose, which is attached to specific protein targets to manipulate what a protein interacts with in the cellular environment.  The interest in this process has been so fierce because these ADP-ribose attachments play fundamental roles throughout biology, from viruses and bacteria to the human body, and have shown promise in the treatment of cancer.  However, it is still not completely understood how these ADP-ribose-protein interactions work and this is largely due to technological gaps. 

Luckily, this project is exploiting recent technological advancements in systems analytics and the manufacturing platform to understand the biology of these interactions and inform the engineering of a new class of polymer therapeutic agents to modify them.  

Project motivation

Nature fabricates precisely defined polymers through an iterative process, adding monomers one after the other in sequence. However manufacturing these materials synthetically is currently challenging.  At lab scale oligonucleotides (oligos) are synthesised by solid phase techniques but this is a difficult process to scale up.  For this reason, developing new manufacturing routes based on liquid phase synthesis and membrane purification is the subject of an on-going collaboration between GSK and Imperial.

This work has created a unique opportunity to make defined sequence synthetic polymers, where monomer sequence can be exploited to control polymer structure.  Current materials are produced industrially by statistical approaches, such as living/controlled polymerisation, inevitably resulting in polydisperse materials.   Furthermore, biologically important polymers, such as those associated with ADP-ribose, are difficult to produce in a flexible manner for characterisation of their function in a discovery framework.  

By developing routes for viable fabrication of these new classes of molecules, this project will open up entirely new potential applications, which will be assessed as part of the programme.  Manufacturing, analytics and biological models will be combined to explore the therapeutic handle of ADP-ribose as a key contact point for manipulating interaction with other entities, such as proteins, DNA or RNA.