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

DOI: 10.1039/D5CB00177C

Authors: Cassandra R. Kennedy (The Francis Crick Institute) , Katherine A. Mcphie (The Francis Crick Institute) , Aini Vuorinen (The Francis Crick Institute) , Jane Dudley-Fraser (The Francis Crick Institute) , Diego Esposito (The Francis Crick Institute) , Sarah Maslen (The Francis Crick Institute) , William J. Mccarthy (The Francis Crick Institute) , Jonathan Pettinger (GSK) , J. Mark Skehel (The Francis Crick Institute) , David House (GSK) , Katrin Rittinger (The Francis Crick Institute) , Jacob Bush (GSK)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Rsc Chemical Biology

State: Published (Approved)
Published: October 2025
Diamond Proposal Number(s): 32711

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 Salmonella and Shigella. 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 Salmonella and show that these proteins are inhibited by compound treatment, representing an exciting starting point for development into specific and potent tool compounds.

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: B21-High Throughput SAXS

Added On: 05/11/2025 15:35

Documents:
d5cb00177c.pdf

Discipline Tags:

Pathogens Antibiotic Resistance Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)