A Prosperity Partnership for the Design, Synthesis, and Evaluation of Next Generation Molecules Beyond Lipinski Space

The pharmaceutical industry makes vital contributions to the UK economy (and healthcare), investing over £8 billion annually in research and development activities. However, the industry faces escalating challenges in discovering new treatments for increasingly complex diseases. The next generation of medicines the sector is focused on goes beyond traditional small-molecule drugs targeting proteins, and represents a new class of molecules capable of interacting with both protein and nucleic acid targets. This emerging category of molecule, termed "chemologics", bridges the space between small molecules and biologics, underpinning innovation which will revolutionise our ability to regulate the function of cell types implicated in the pathogenesis of a range of disease states. To successfully innovate in this area, new approaches are needed for the design, synthesis, and testing of these emerging modalities. The University of Strathclyde has established (from 2009) a highly productive research partnership with GSK, a research-focused global pharmaceutical company, which has centred around innovative approaches to medicine design. In the current proposal, we aim to escalate this successful collaborative endeavour by addressing the challenges associated with the discovery and synthesis of new chemical modalities which reside outside of the property space defined by the vast majority of existing small molecule medicines. We aim to realise our vision of exploiting new modalities for disease management through three Scientific Themes that have been co-developed with our industrial partner, and which reflect current priorities in pharmaceutical research and development. Firstly, Theme 1 will concentrate on tackling significant challenges within the oligonucleotide arena. Specifically, we aim to transform synthetic protocols necessary for producing these modalities sustainably. Another crucial deliverable is enhancing intracellular delivery of oligonucleotide species, where we will leverage emerging technology platforms developed in collaboration with GSK to enable efficient synthesis and biological assessment of oligonucleotide-cell penetrating peptide constructs. Secondly, Theme 2 will focus on developing novel heterobifunctional moieties to target RNA and its interacting partners. While entities like PROTACs have gained traction, a raft of other opportunities exist for modulating protein and nucleic acid targets through direct degradation or manipulation of RNA processing. Again, through leveraging technologies jointly developed by GSK and UoS, we will establish a high-throughput platform to design, synthesise, and test an array of next-generation heterobifunctional reagents. Lastly, Theme 3 will integrate Artificial Intelligence/Machine Learning (AI/ML), modelling, and related data analytics approaches to both inform on the design of new synthetic processes, and also deliver a more detailed understanding of structure-property relationships between the novel molecular constructs being designed and their cognate molecular targets. Addressing these challenges offers the potential to provide a step change in the types of molecule the pharmaceutical sector is capable of prosecuting, thus facilitating the development of next-generation medicines which address deficiencies in our current armamentarium against disease. Beyond the tangible scientific deliverables, this Prosperity Partnership will also equip future researchers with the necessary skills for advancing pharmaceutical research in the long-term, by providing them with an immersion in the preparation and evaluation of molecules which are differentiated from more traditional drug assets.