Towards Inhibition of Oncogenic RhoA Signaling using Stapled Peptides
type: CreativeWork
description: Given that cancer is the second leading cause of death worldwide with its major treatments, surgery and chemotherapy, causing significant side-effects, diminished quality of life and leaving a risk of recurrence, more efficient and less toxic treatments are needed. A challenge in targeted therapy is the "undruggability" or difficulty in developing traditional small molecule inhibitors to many of the identified oncogenic targets, including the Ras superfamily of small GTPases. Peptide therapeutics are emerging as promising new modalities to more efficiently inhibit these "undruggable" targets. RhoA is a member of the Rho family within the Ras superfamily of small GTPases and is a major regulator of cytoskeletal remodelling, cell migration and proliferation. It is found overexpressed, overactivated or mutated (eg. RhoA G17V) in many cancers including gastric, testicular, hepatocellular carcinoma and lymphomas, and is associated with invasion, mestastasis, therapy resistance and poor prognosis. Therefore, RhoA is a potential therapeutic target in cancers with high RhoA activity. Given the relatively large and shallow surface of RhoA that interacts with its downstream effectors, deep, hydrophobic pockets suitable for small molecule inhibitors are nonexistent. The larger size of peptide inhibitors may, therefore, lead to more specific and tighter-binding candidates for further drug development. This work presents the investigation of the HR1a domain from the RhoA effector, PRK1/PKN1 kinase, as a starting point for peptide inhibitor design. HR1a binds to RhoA with nanomolar affinity and forms an anti-parallel coiled coil. This dissertation starts with mutagenesis studies on the RhoA-binding residues of HR1a to identify the minimal region of hotspots, which was found to encompass a 17-mer, α-helical sequence (residues 48-63) within the N-terminal helix of HR1a. A starting peptide scaffold made of this minimal sequence (called P1) was synthesised and assessed in Circular Di…
abstract: Given that cancer is the second leading cause of death worldwide with its major treatments, surgery and chemotherapy, causing significant side-effects, diminished quality of life and leaving a risk of recurrence, more efficient and less toxic treatments are needed. A challenge in targeted therapy is the "undruggability" or difficulty in developing traditional small molecule inhibitors to many of the identified oncogenic targets, including the Ras superfamily of small GTPases. Peptide therapeutics are emerging as promising new modalities to more efficiently inhibit these "undruggable" targets. RhoA is a member of the Rho family within the Ras superfamily of small GTPases and is a major regulator of cytoskeletal remodelling, cell migration and proliferation. It is found overexpressed, overactivated or mutated (eg. RhoA G17V) in many cancers including gastric, testicular, hepatocellular carcinoma and lymphomas, and is associated with invasion, mestastasis, therapy resistance and poor prognosis. Therefore, RhoA is a potential therapeutic target in cancers with high RhoA activity. Given the relatively large and shallow surface of RhoA that interacts with its downstream effectors, deep, hydrophobic pockets suitable for small molecule inhibitors are nonexistent. The larger size of peptide inhibitors may, therefore, lead to more specific and tighter-binding candidates for further drug development. This work presents the investigation of the HR1a domain from the RhoA effector, PRK1/PKN1 kinase, as a starting point for peptide inhibitor design. HR1a binds to RhoA with nanomolar affinity and forms an anti-parallel coiled coil. This dissertation starts with mutagenesis studies on the RhoA-binding residues of HR1a to identify the minimal region of hotspots, which was found to encompass a 17-mer, α-helical sequence (residues 48-63) within the N-terminal helix of HR1a. A starting peptide scaffold made of this minimal sequence (called P1) was synthesised and assessed in Circular Di…
author: Qiu Mexia de Azeredo, Carolina Ting-Ting
language: eng
keywords: cancer, molecular dynamics, molecular dynamics simulations, non-proteinogenic amino acids, peptide engineering, peptide inhibitors, peptide therapeutics, PRK1/PKN1, Rac1, Rational-design, RhoA, small GTPase, stapled peptides, Structure-based design, targeted therapy for cancer, undruggable target
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/7fe87c45-2944-4f2d-a3f2-75391559e1f1/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2024-04-19
date modified: 2026-07-22T22:24:13Z
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.117705