An, Jinsu Kim, So Yeon Yang, Eun Gyeong Chung, Hak Suk 2024-01-12T03:31:43Z 2024-01-12T03:31:43Z 2022-04-13 2022-04 1420-3049 https://pubs.kist.re.kr/handle/201004/76756 Recognition of intracellular lipopolysaccharide (LPS) by Caspase-4 (Casp-4) is critical for host defense against Gram-negative pathogens. LPS binds to the N-terminal caspase activation and recruitment domain (CARD) of procaspase-4, leading to auto-proteolytic activation followed by pro-inflammatory cytokine release and pyroptotic cell death. Aberrant hyper-activation of Casp-4 leads to amplification of the inflammatory response linked to sepsis. While the active site of a caspase has been targeted with peptide inhibitors, inhibition of LPS-Casp-4 interaction is an emerging strategy for the development of selective inhibitors with a new mode of action for treating infectious diseases and sepsis induced by LPS. In this study, a high-throughput screening (HTS) system based on fluorescence polarization (FP) was devised to identify inhibitors of the LPS and Casp-4 interaction. Using HTS and IC50 determination and subsequently showing inhibited Casp-4 activity, we demonstrated that the LPS-Casp-4 interaction is a druggable target for Casp-4 inhibition and possibly a non-canonical inflammatory pathway. English Multidisciplinary Digital Publishing Institute (MDPI) A Fluorescence-Polarization-Based Lipopolysaccharide-Caspase-4 Interaction Assay for the Development of Inhibitors Article 10.3390/molecules27082458 1 Molecules, v.27, no.8, pp.2458 Molecules 27 8 2458 Y scie scopus 000785454300001 Biochemistry & Molecular Biology Chemistry, Multidisciplinary Biochemistry & Molecular Biology Chemistry Article PYROPTOSIS CASPASE-11 ACTIVATION TRIAL caspase-4 lipopolysaccharides caspase activation and recruitment domain (CARD) non-canonical inflammasome high-throughput screening fluorescence polarization