Louise Walport
Group Leader
Imperial College London and The Francis Crick Institute
Talk Information
New Fronteirs in Peptide Science
19 June 2025, 04:50pm - 05:05pm, in the Pacific Jewel Ballroom
L72 – Exploiting Covalency in mRNA Displayed Cyclic Peptides
Dr. Louise Walport is a Senior Lecturer in the Department of Chemistry at Imperial College London and a Group Leader at the Francis Crick Institute. Her research focuses on the development of cyclic peptide tools to investigate protein-protein interactions, particularly those involved in epigenetic regulation and immune responses.
Academic Background
Dr. Walport obtained her MChem in Chemistry from Magdalen College, University of Oxford, in 2009. She completed her DPhil in Chemical Biology at the University of Oxford in 2014, working under Professors Chris Schofield and Christina Redfield. Her doctoral research employed biochemical and structural techniques to study 'reader' and 'eraser' proteins involved in epigenetics. Following her Ph.D., she conducted postdoctoral research at Oxford before receiving a Global Marie Skłodowska-Curie Fellowship to work with Professor Hiroaki Suga at the University of Tokyo. She returned to Oxford for a final year of her fellowship in Professor Schofield’s lab. In 2018, Dr. Walport established her independent research group at the Francis Crick Institute, concurrent with her appointment at Imperial College London.
Research Focus
Dr. Walport's laboratory specializes in chemical biology, with an emphasis on designing and utilizing cyclic peptides to probe and modulate protein-protein interactions. Her team employs mRNA display technologies to discover high-affinity cyclic peptides targeting proteins implicated in epigenetic regulation, such as bromodomains and peptidylarginine deiminases, PADIs. This research aims to elucidate the mechanisms of these proteins and develop novel therapeutic strategies.
Notable Contributions
Dr. Walport has significantly advanced the understanding of protein-protein interactions through her development of cyclic peptide inhibitors. Her work includes the discovery of covalent cyclic peptide inhibitors of PADI4 using mRNA-display with genetically encoded electrophilic warheads, as well as the identification of cyclic peptides targeting the BRD3 extraterminal domain. These contributions have provided valuable insights into the regulation of epigenetic enzymes and their roles in disease.
Professional Engagements
Beyond her research, Dr. Walport is actively involved in teaching and mentoring at Imperial College London. She contributes to the scientific community through her participation in conferences and collaborative projects. Her interdisciplinary approach bridges chemistry and biology, fostering innovations in the development of chemical tools for biomedical research.
Through her pioneering work in chemical biology, Dr. Louise Walport continues to make significant contributions to the understanding and manipulation of protein interactions, with implications for therapeutic development.
Exploiting Covalency in mRNA-Displayed Cyclic Peptides
Department of Chemistry, Molecular Sciences Research Hub, Imperial College, 80 Wood Lane, London, W12 OBZ, UK; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
mRNA-display-based cyclic peptide discovery platforms, such as RaPID, provide powerful routes to rapidly identify tight binding ligands to almost any target of choice. To date most hits have been identified by affinity panning against a target to yield tight but reversible binders. With the increased interest in covalency in drugs and chemical probes, however, we have been working towards modifying mRNA-display strategies to identify covalent ligands exploiting both photoreactive and electrophilic warheads.
Taking advantage of the amazing versatility of the ribosome, we have been incorporating a range of reactive moieties into RaPID libraries. Introducing photoreactive p-benzoyl-L-phenylalanine into libraries we developed photocrosslinking-RaPID (XL-RaPID), which can accelerate the discovery of cyclic peptides that photocrosslink to a target of interest.1 Using this approach we have identified de novo covalent probes to the second bromodomain of BRD3 that can label it selectively even in complex cell lysates. Building on this strategy we have extended XL-RaPID to support conversion of a potent reversible cyclic peptide binder into an efficient crosslinking probe using PCSK9, a protein involved in the regulation of LDL cholesterol levels, as a model target. Finally, moving beyond photocrosslinking, we have recently introduced cysteine-reactive electrophiles into RaPID libraries. Using these new libraries we have identified potent irreversible inhibitors of the arginine deiminase PAD4 and have explored the ability of tight binding peptides to drive covalency at different cysteine sites.
[1] Wu Y, Bertran MT, Joshi D, Maslen SL, Hurd C, Walport LJ, Commun Chem, 2023, 6, 103.
[2] Mathiesen I, Calder EDD, Kunzelmann S, Walport LJ, Commun Chem, 2024, 7, 304.