Joel Mackay with Toby Passioura, Richard Payne and Louise Walport (Crick Institute)
Antibodies are extremely powerful molecular scaffolds because of their ability to specifically recognize a vast array of targets while retaining the same three-dimensional shape. This property (among others) has led to the development of a rapidly increasing number of antibody-based drugs. However, because of their large size and their requirement for disulphide bonds, they are not well suited for intracellular targets.
We are using RaPID mRNA display technology to develop proteins and cyclic peptides based around other scaffolds that can zero in on a variety of protein targets of interest to us – mostly proteins involved in regulating transcription in normal human biology or in disease states. RaPID allows the creation of exceedingly large libraries (10^12 to 10^14 members) of polypeptides and also permits the incorporation of unnatural amino acids. Together, these features yield massive chemical diversity – just what we think we need to create ligands that can modulate the function of challenging protein targets (like transcription factors!). Such ligands could be powerful tools for dissecting protein function and – ultimately – could be valuable starting points for a new generation of protein-based therapeutics.