Fragment Screening to Identify Inhibitors Targeting Ribosome Binding of Shiga Toxin 2

• Published in: ACS infectious diseases Vol. 10; no. 8; pp. 2814 - 2825
• Main Authors: Rudolph, Michael J., Tsymbal, Anastasiia M., Dutta, Arkajyoti, Davis, Simon A., Algava, Benjamin, Roberge, Jacques Y., Tumer, Nilgun E., Li, Xiao-Ping
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09.08.2024
• Subjects: Binding Sites; Humans; Protein Binding; Ribosomes - drug effects; Ribosomes - metabolism; Shiga Toxin 2 - antagonists & inhibitors; Shiga Toxin 2 - chemistry; Shiga Toxin 2 - metabolism; Shiga-Toxigenic Escherichia coli - drug effects; Shiga-Toxigenic Escherichia coli - metabolism; depurination inhibition; fragment-based drug discovery; Shiga toxins; X-ray crystal structure; ribosome binding; ribosome-inactivating protein
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.4c00224

Shiga toxins are the main virulence factors of Shiga toxin producing E. coli (STEC) and S. dysenteriae. There is no effective therapy to counter the disease caused by these toxins. The A1 subunits of Shiga toxins bind the C-termini of ribosomal P-stalk proteins to depurinate the sarcin/ricin loop. The ribosome binding site of Shiga toxin 2 has not been targeted by small molecules. We screened a fragment library against the A1 subunit of Shiga toxin 2 (Stx2A1) and identified a fragment, BTB13086, which bound at the ribosome binding site and mimicked the binding mode of the P-stalk proteins. We synthesized analogs of BTB13086 and identified a series of molecules with similar affinity and inhibitory activity. These are the first compounds that bind at the ribosome binding site of Stx2A1 and inhibit activity. These compounds hold great promise for further inhibitor development against STEC infection.