New approaches for high-throughput peptide-based ligand discovery

High-throughput approaches for peptide discovery have been dramatically boosted by the development of genetically-encoded methods. In these, the DNA encoding a molecule is connected to the molecule itself, as illustrated above (blue/black lines are RNA/DNA, and spheres are amino acids). This allows binders to a given protein to be very efficiently separated from non-binders, in principle isolating and identifying from a single initial molecule. This is a very powerful concept, but linear sequences of the 20 canonical amino acids are often of limited use in biological systems. Adding chemical complexity, still in a genetically encoded way, can address this issue. Two common approaches for this in the context of mRNA display are to reassign codons to non-canonical building blocks (genetic code reprogramming) and to add new functionality after translation through chemical means (chemoselective transformations). We work on development of new methods in both areas (and look at applications of these, described further below).

de novo macrocyclic peptide ligand discovery for disease-relevant targets

Macrocyclic peptides are receiving increasing attention as a drug modality to can tackle challenges that are resistant to traditional small molecules. Similar to antibodies, the large contact surface allows for highly precise and strong binding to a drug target. Unlike antibodies, however, macrocyclic peptides are defined chemical entities that can be optimised, scaled up, stored, and in some cases even cross biological membranes. This makes them very powerful starting points for drug development.

We apply new and existing methodologies for macrocyclic peptide discovery by mRNA display, incorporating genetic code reprogramming and/or chemical modification to introduce valuable additions. General areas of interest include immunology, anti-infective agents, and anti-cancer agents.

Specific targets we are currently or have previously worked on include