Development of peptide inhibitors as molecular therapeutics against tandem-repeat proteins
type: CreativeWork
description: Tandem-repeat (TR) domains occur in approximately one third of all proteins, yet these domains are less well understood compared with their globular counterparts. TR proteins act as molecular scaffolds that facilitate protein-protein interactions (PPIs) in diverse biological contexts. In disease pathologies such as cancers, misfolded, mutated or deregulated TR function is often the cause. However, targeting tandem-repeat proteins is challenging due to their flat and large interaction interfaces. In this thesis, I have explored the development of peptide-based inhibitors of PPIs involving two targets, Tankyrase (TNKS) the Anaphase Promoting Complex/Cyclosome (APC/C-Cdc20). TNKS belong to the poly-ADP-ribose polymerases (PARP) family of enzymes that PARylate their substrates, leading to ubiquitination and subsequent degradation. TNKS bind their protein substrates through an ankyrin-repeat domain comprising five so-called Ankyrin Repeat Clusters (ARCs). TNKS is of particular therapeutic interest in cancers due to its PARylation of Axin1, a subunit of the β-catenin destruction complex. We investigated the design of peptide inhibitors of TNKS ARC domains through a structure guided approach. We first attempted to expand the range of biophysical assays to assess ligand binding to TNKS ARCs. We then designed and tested a set of linear and chemically constrained peptides for their ability to bind to the ARCs. The APC/C is an E3 ubiquitin ligase that has broad substrate-specificity via its two WD40-domain co-activators, Cdc20 and Cdh1, which recognise three peptide motifs (degrons) on its substrates: the D-box, the KEN box and the ABBA motif. The regulation of mitotic exit is tightly controlled by modulating the levels of Cdc20 and Cdh1 through different stages of the cell cycle. Cdc20 overexpression is associated with many cancers. Currently, no specific inhibitors of the APC/C-Cdc20 exist in the clinic or in clinical trials. We designed a series of synthetic peptides based …
abstract: Tandem-repeat (TR) domains occur in approximately one third of all proteins, yet these domains are less well understood compared with their globular counterparts. TR proteins act as molecular scaffolds that facilitate protein-protein interactions (PPIs) in diverse biological contexts. In disease pathologies such as cancers, misfolded, mutated or deregulated TR function is often the cause. However, targeting tandem-repeat proteins is challenging due to their flat and large interaction interfaces. In this thesis, I have explored the development of peptide-based inhibitors of PPIs involving two targets, Tankyrase (TNKS) the Anaphase Promoting Complex/Cyclosome (APC/C-Cdc20). TNKS belong to the poly-ADP-ribose polymerases (PARP) family of enzymes that PARylate their substrates, leading to ubiquitination and subsequent degradation. TNKS bind their protein substrates through an ankyrin-repeat domain comprising five so-called Ankyrin Repeat Clusters (ARCs). TNKS is of particular therapeutic interest in cancers due to its PARylation of Axin1, a subunit of the β-catenin destruction complex. We investigated the design of peptide inhibitors of TNKS ARC domains through a structure guided approach. We first attempted to expand the range of biophysical assays to assess ligand binding to TNKS ARCs. We then designed and tested a set of linear and chemically constrained peptides for their ability to bind to the ARCs. The APC/C is an E3 ubiquitin ligase that has broad substrate-specificity via its two WD40-domain co-activators, Cdc20 and Cdh1, which recognise three peptide motifs (degrons) on its substrates: the D-box, the KEN box and the ABBA motif. The regulation of mitotic exit is tightly controlled by modulating the levels of Cdc20 and Cdh1 through different stages of the cell cycle. Cdc20 overexpression is associated with many cancers. Currently, no specific inhibitors of the APC/C-Cdc20 exist in the clinic or in clinical trials. We designed a series of synthetic peptides based …
author: Eapen, Rohan
language: eng
keywords: Drug discovery, Peptides, Tankyrase, APC/C, Cdc20
license: https://www.repository.cam.ac.uk/bitstreams/6d2c52f6-5ec5-473c-a98f-2df62ebc06f6/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2019-12
date modified: 2026-07-22T22:23:56Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.59298