Within the Synthesis and Methodology subgroup we aim to push forward the boundaries of what is chemically possible, with the ultimate goal of applying the chemistry to relevant biological problems.
Bioconjugation methodology constitutes a large part of the research performed in the Spring group. Bioconjugation, the attachment of a compound to a biological molecule, is used for a variety of functions, from designing novel materials, to studying biological processed in vitro and in vivo (for example, by attaching fluorophores to key proteins), to creating targeted therapeutics (for example Antibody-Drug Conjugates, ADCs). Traditional bioconjugation techniques make use of nucleophilic amino acid side chains, such as lysine or cysteine. Lysines are ubiquitous on protein surfaces and so are readily available for conjugation, although this can lead to selectivity issues. Cysteine residues are the least abundant amino acid, and therefore offer opportunities for selective, individual conjugation reactions. However, cysteines are sometimes not available on a protein of interest. For this reason, it would be useful to have other means of attaching molecules to proteins, for example at other amino acid residues. Current projects in the Synthesis and Methodology subgroup are focused on developing the use of visible light photoredox catalysis for bioconjugation at under-explored amino acid side chains.
The dysregulation of a protein level or its activity are a major cause of disease. We are researching recent advances to address this dysregulation, such as small-molecule protein degraders or multi-target directed ligands. These approaches rely on the discovery of 'dual-binding ligands' bearing two clearly differentiated pharmacophoric moieties. Their precise combination can promote ubiquitination of a given target leading to its depletion (selective protein degraders) or modulate simultaneously the activity of different targets leading to synergistic effects (multi-target compounds). Such compounds are valuable tools for biological understanding and are potential chemotherapeutics.
Other work in this area focuses on improving efficacy of ADCs. Compounds that show good potency against a range of cancer cell lines would make developing ADCs against new cancer phenotypes more accessible. To this end, members of the group are exploring new and efficient routes to bioactive natural products, with the end goal of using them as payloads in ADCs.
Many industrial screening collections for drug discovery comprise of predominantly 'flat' aromatic compounds. It has been argued that a lack of structural diversity among screening compounds has led to several failed high-throughput screening campaigns. Diversity-Oriented Synthesis (DOS) aims to generate structurally diverse and stereochemically complex molecules starting from simple, commercially-available building blocks. Using this methodology, many structurally distinct compounds with a high fraction of sp3-hybridised atoms can be produced to enrich screening collections. This opens up the opportunity to find novel binding modes and therapeutic effects. Past projects in DOS have led to the generation of the Spring Group Compound Collection, a screening library which is available throughout the University and beyond.