Flagship 3 tackles the grand challenge of producing important natural and designed peptides and proteins to translate them into products for a range of industries. Researchers within this Flagship are involved in projects within our Decode and Develop themes.
Flagship 3 researchers use both traditional chemical synthesis techniques and biosynthetic strategies that harness naturally occurring enzymes. Many natural peptides and proteins contain post-translational modifications (PTMs), which are small chemical ‘add-ons’ that can enhance structure and function. Currently, these modifications are very difficult to introduce to peptides and proteins in the laboratory, and thus there is an additional focus within this Flagship on developing new synthetic strategies for introducing PTMs.
Our researchers use established synthetic chemistry methods, including solid-phase peptide synthesis, whilst developing modern strategies in peptide ligation, protein expression, and protein modification. Our expertise in chemical synthesis enables us to manufacture important peptide and protein targets, as well as translate the complexity of larger proteins into smaller peptides for commercialisation. We are particularly interested in developing chemical modification techniques using acyl hydrazide chemistry, electrochemical strategies and through the use of microfluidics.
Our researchers are also identifying new peptides of interest using mRNA display technology including the Random nonstandard Peptide Integrated Discovery (RaPID) platform, a powerful tool for high-throughput peptide screening. We have already used this technique to identify inhibitors of therapeutically relevant targets, including the SARS-CoV-2 spike protein and human acid sensing ion channel 1a.
We are investigating the ways in which peptides of both ribosomal and non-ribosomal origin are biosynthesised in Nature. We are particularly interested in the biosynthesis of glycopeptide antibiotics, epoxyketone proteasome inhibitors, and bicyclic depsipeptide histone deacetylase inhibitors, which have important future applications in the treatment of infectious diseases and cancer. We will harness these biosynthetic processes in the laboratory for sustainable production of a wide range of bioactive peptides.
Our researchers are studying the evolution of enzymatic pathways to inform our protein engineering and enzyme design strategies. We are especially interested in designing peptide and protein-modifying enzymes. We are applying cutting-edge machine learning and bioinformatics approaches to develop new enzymes to catalyse reactions previously unachievable in Nature or the laboratory thereby expanding new frontiers in peptide and protein engineering.