TY - JOUR T1 - Targeting redox regulatory site of protein kinase B impedes neutrophilic inflammation in lung injury JF - bioRxiv DO - 10.1101/264184 SP - 264184 AU - Po-Jen Chen AU - I-Ling Ko AU - Chia-Lin Lee AU - Hao-Chun Hu AU - Fang-Rong Chang AU - Yang-Chang Wu AU - Yann-Lii Leu AU - Chih-Ching Wu AU - Cheng-Yu Lin AU - Chang-Yu Pan AU - Yung-Fong Tsai AU - Tsong-Long Hwang Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/04/13/264184.abstract N2 - Neutrophil activation has a pathogenic effect in inflammatory diseases. Protein kinase B (PKB)/AKT regulates diverse cellular responses. However, the significance of AKT in neutrophilic inflammation is still not well understood. Here, we identified CLLV-1 as a novel AKT inhibitor. CLLV-1 inhibited respiratory burst, degranulation, chemotaxis, and AKT phosphorylation in activated human neutrophils and dHL-60 cells. Significantly, CLLV-1 blocked AKT activity and covalently reacted with AKT Cys310 in vitro. The AKT309-313 peptide-CLLV-1 adducts were determined by NMR or mass spectrometry assay. The alkylation agent-conjugated AKT (reduced form) level was also inhibited by CLLV-1. Additionally, CLLV-1 ameliorated lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. CLLV-1 acts as a covalent allosteric AKT inhibitor by targeting AKT Cys310 to restrain inflammatory responses in human neutrophils and LPS-induced ALI in vivo. Our findings provide a mechanistic framework for redox modification of AKT that may serve as a novel pharmacological target to alleviate neutrophilic inflammation. ER -