Targeting the Rho1 GTPase signalling pathway in Aspergillus fumigatus
type: CreativeWork
description: For individuals with compromised immune systems, Aspergillus fumigatus has emerged as one of the most common airborne fungal pathogens in recent decades. In immunosuppressed patients, inhalation of A. fumigatus spores can initiate life-threatening invasive aspergillosis (IA) with mortality rates up to 90%. The high mortality is largely due to a limited arsenal of antifungal drugs and emerging resistance and also the poor diagnosis. At present, the treatment for this fungal infection is dominated by three antifungal classes. Polyenes and azoles target the fungal cell membrane, and echinocandins target β-glucan synthesis in the fungal cell wall. However, they all have significant drawbacks in terms of toxicity, drug-drug interactions and/or efficacy. The current efforts are to structurally and chemically validate new targets that are genetically proven as essential in A. fumigatus. One such protein AfRho1 is a Rho GTPase, plays essential roles in fungal physiology and cell wall organization. In this research, I combined X-ray crystallography and fragment-based small molecule screening by BLI (Biolayer interferometry) to investigate the ligandability of AfRho1. Using X-ray crystallography, the structure of AfRho1 was solved and a complex structure with one of the hit fragments was obtained. The complex structure showed that this fragment molecule bound to AfRho1 in a 2:1 molar ratio, and the fragment binding pocket is conserved with the human orthologue protein HsRhoA. Structure analysis shows that the pocket is located at the previously validated interaction interface between Rho GTPases and the upstream activation GEF (Guanine nucleotide exchange factor) proteins. Therefore, in this research I have identified a lead molecule that could be used to develop inhibitors against AfRho1 and HsRhoA by inhibiting the corresponding GEF proteins mediated nucleotide exchange. Rom2, a Rho1 GTPase guanine nucleotide exchange factor (GEF), plays an essential role in the fungal cell…
abstract: For individuals with compromised immune systems, Aspergillus fumigatus has emerged as one of the most common airborne fungal pathogens in recent decades. In immunosuppressed patients, inhalation of A. fumigatus spores can initiate life-threatening invasive aspergillosis (IA) with mortality rates up to 90%. The high mortality is largely due to a limited arsenal of antifungal drugs and emerging resistance and also the poor diagnosis. At present, the treatment for this fungal infection is dominated by three antifungal classes. Polyenes and azoles target the fungal cell membrane, and echinocandins target β-glucan synthesis in the fungal cell wall. However, they all have significant drawbacks in terms of toxicity, drug-drug interactions and/or efficacy. The current efforts are to structurally and chemically validate new targets that are genetically proven as essential in A. fumigatus. One such protein AfRho1 is a Rho GTPase, plays essential roles in fungal physiology and cell wall organization. In this research, I combined X-ray crystallography and fragment-based small molecule screening by BLI (Biolayer interferometry) to investigate the ligandability of AfRho1. Using X-ray crystallography, the structure of AfRho1 was solved and a complex structure with one of the hit fragments was obtained. The complex structure showed that this fragment molecule bound to AfRho1 in a 2:1 molar ratio, and the fragment binding pocket is conserved with the human orthologue protein HsRhoA. Structure analysis shows that the pocket is located at the previously validated interaction interface between Rho GTPases and the upstream activation GEF (Guanine nucleotide exchange factor) proteins. Therefore, in this research I have identified a lead molecule that could be used to develop inhibitors against AfRho1 and HsRhoA by inhibiting the corresponding GEF proteins mediated nucleotide exchange. Rom2, a Rho1 GTPase guanine nucleotide exchange factor (GEF), plays an essential role in the fungal cell…
author: Wei, Wenfan
language: eng
keywords: Aspergillus fumigatus, Rho GTPase, fragment screen, Rom2, GEF, CNH domain
date published: 2017
date modified: 2026-07-24T02:08:32Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee