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Drug discovery for inhibition of the GEF-H1/RhoA pathway

Gathmann, Clara; (2023) Drug discovery for inhibition of the GEF-H1/RhoA pathway. Doctoral thesis (Ph.D), UCL (University College London).

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Fibrosis and inflammation in human tissues are common markers for diseases like epithelial cancers, organ injuries and infections, and common ocular disorders. The guanine exchange factor H1 (GEF-H1) activates RhoA to control cytoskeletal responses during fibrosis and inflammation and is notably overexpressed in ocular tissues suffering from retinopathies and uveitis. Based on the GEF-H1/RhoA protein-protein interaction, α-helical peptides were previously designed that inhibit GEF-H1 signalling in cell culture and in vivo models of ocular diseases. Furthermore, a virtual screening approach discovered a small molecule peptidomimetic (Sm762) with micromolar activity against GEF-H1 in cell culture models of ocular disease. The overall purpose of this thesis was to design improved small molecules compared to Sm762 rationally. Molecular models were built to predict Sm762 binding in GEF-H1, and the conformational landscape of Sm762 was characterised to support its α-helix mimicry hypothesis. Aided by the developed in silico tools, 37 Sm762 analogues were designed, synthesised, and biologically characterised to generate a structure-activity relationship (SAR) study. This approach yielded improved GEF-H1 inhibitors compared to Sm762 in a GEF-H1 overexpression model, which will be further characterised in disease models. In vitro assays using recombinant GEF-H1 were further developed and validated against the first-generation inhibitors. The first steps to develop additional structurally unrelated GEF-H1 inhibitors were made, including characterising a stapled peptide in these assays and the identification of five new hits from a DNA-encoded library screen. Overall, this thesis contributes to validating GEF-H1 as a target in ocular inflammatory and fibrotic diseases. Improved small molecules compared to the first-generation inhibitors in cell culture disease models were generated, and tools and models were developed to facilitate future drug design studies against GEF-H1 generally.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Drug discovery for inhibition of the GEF-H1/RhoA pathway
Language: English
Additional information: Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
Keywords: Medicinal Chemistry, RhoA, GEF-H1, Occular disorders
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10171355
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