WNT-mediated signaling relay in stem cells and oncogenesis - from basic biology to applications

Generation and identification of short active peptides against WNT pathway therapeutic targets

Experienced researcher 3 (ER3) project

Supervision: Chris Ullman

Lab webpage:  http://www.isogenica.com

Aim:
To generate and identify short active peptides against WNT pathway targets using CIS display

Methodology:
ER3 will use the proprietary CIS display system to optimise agonist or antagonists for the protein-protein or protein-peptide interactions identified through WntsApp partners. Particular focus will be on FZD5, FZD7, RNF43 and AXIN (collaboration Schulte, Rüdiger, Friedler, Koo, international secondment: Maurice). Because the process does not require transformation into bacterial cells, ER3 can rapidly construct these large libraries according to a specific design. ER3 will use this technology to develop libraries using rational designs and combinatorial methods, based upon knowledge of the targets and their natural protein-protein interactions, to identify novel binders. There is also scope to develop libraries, using CIS display and chemical modifications, which will conformationally ‘lock’ the peptides for improved affinity and efficacy (private sector secondment: Pepscan).

Collaborators:
Maurice, Schulte, Rüdiger, Friedler, Koo, Pepscan

Project goals:
ER3 will generate lead compounds with high affinity and efficacy for WNT target proteins FZD5, FZD7, RNF43 and AXIN

Risk assessment and contingency plans:
Using this approach Isogenica has previously succeeded developing short active peptides that have antibody-like, subnanomolar, affinities against therapeutic targets.

Key publications:

  1. Odegrip R, Coomber D, Eldridge B, Hederer R, Kuhlman PA, Ullman C, FitzGerald K, McGregor D. (2004) CIS display: In vitro selection of peptides from libraries of protein-DNA complexes. PNAS, 101(9):2806-10
  2. Eldridge B, Cooley RN, Odegrip R, McGregor DP, Fitzgerald KJ, Ullman CG. (2009). An in vitro selection strategy for conferring protease resistance to ligand binding peptides. PEDS 22(11):691-8
  3. Ullman CG, Frigotto F and Cooley RN. (2011) In vitro methods for peptide display and their applications. Briefings in Funct Genom 10 (3) 125-134