MACKAY & MATTHEWS LAB

Protein structure, function and engineering

Our first mRNA display paper hits the internet in PNAS

Oct 13, 2020

A big paper for us – out now here! Working with Louise Walport and Toby Passioura, who were themselves working with Hiroaki Suga at the University of Tokyo at the time, we have used Suga’s RaPID version of mRNA display to discover cyclic peptide inhibitors of the BRD3 and BRD4 bromodomains that have nM to pM affinities and – in some cases – very high specificity compared to small-molecule inhibitors. One of the cool things about the RaPID setup is that you can incorporate unnatural amino acids – and our peptides all had one or more acetyllysine residues.
We see a wide range of binding modes, giving hints about ways that one could design much more specific bromodomain inhibitors than are currently possible by targeting other parts of the BDs than just the acetyllysine binding site. The downside is that so far these cyclic peptides have not displayed significant cell permeability – but one step at a time! Fantastic work led by Karishma Patel, with James Walshe, Paul Solomon, Jason Low, Ana Silva, Lorna Wilkinson-White, Charlotte Frank, Jacqui Matthews and Mitchell Guss all involved too – along with third year student Kevork Mouridian and Dan Tran and Alex Norman from Richard Payne’s lab in Chemistry.

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