Covalent fragment screening to inhibit the E3 ligase activity of bacterial NEL enzymes SspH1 and SspH2

As the global fight against antimicrobial resistance in bacteria becomes increasingly pressing, new tool compounds are needed to study and evaluate novel therapeutic targets. Here, cysteine-directed fragment-based drug discovery is coupled with high throughput chemistry direct-to-biology screening to target the catalytic cysteine of a family of bacterial effector proteins, the novel E3 ligases (NELs) from <i>Salmonella</i> and <i>Shigella</i>. These effector E3 ligases are attractive as potential drug targets because they are delivered into host cells during infection, have no human homologues and disrupt host immune response to infection. We successfully identify hit compounds against the SspH subfamily of NELs from <i>Salmonella</i> and show that these proteins are inhibited by compound treatment, representing an exciting starting point for development into specific and potent tool compounds.

Authors

Institutions

Publication Details

Journal
RSC Chemical Biology
Published
2025-10-28
DOI
https://doi.org/10.1039/d5cb00177c
Citations
2
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
1.61

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Covalent fragment screening to inhibit the E3 ligase activity of bacterial NEL enzymes SspH1 and SspH2

Mark Skehel, David House, Aini Vuorinen, Diego Esposito et al.
2 citations
RSC Chemical Biology
Protein Degradation and Inhibitors
1.61
article

Covalent fragment screening to inhibit the E3 ligase activity of bacterial NEL enzymes SspH1 and SspH2

Mark Skehel, David House, Aini Vuorinen, Diego Esposito, Jane Dudley-Fraser, William J. McCarthy, Jacob T. Bush, Katherine A. McPhie, Katrin Rittinger, Sarah Maslen, Cassandra R. Kennedy, Jonathan Pettinger
article en
2 citations

Abstract

As the global fight against antimicrobial resistance in bacteria becomes increasingly pressing, new tool compounds are needed to study and evaluate novel therapeutic targets. Here, cysteine-directed fragment-based drug discovery is coupled with high throughput chemistry direct-to-biology screening to target the catalytic cysteine of a family of bacterial effector proteins, the novel E3 ligases (NELs) from <i>Salmonella</i> and <i>Shigella</i>. These effector E3 ligases are attractive as potential drug targets because they are delivered into host cells during infection, have no human homologues and disrupt host immune response to infection. We successfully identify hit compounds against the SspH subfamily of NELs from <i>Salmonella</i> and show that these proteins are inhibited by compound treatment, representing an exciting starting point for development into specific and potent tool compounds.

RSC Chemical BiologyVol. 7(1)
Age UK (GB), The Francis Crick Institute (GB)
Wellcome Trust, Francis Crick Institute, Medical Research Council, Engineering and Physical Sciences Research Council
Openalex Percentile: Top 14%
Protein Degradation and Inhibitors
1.61
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.