Fragment Screening to Identify Inhibitors Targeting Ribosome Binding of Shiga Toxin 2.
ACS Infect Dis
; 10(8): 2814-2825, 2024 Aug 09.
Article
en En
| MEDLINE
| ID: mdl-38873918
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Ribosomas
/
Toxina Shiga II
Límite:
Humans
Idioma:
En
Revista:
ACS Infect Dis
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos