7QH1

Discovery and development of a novel inhaled antivirulence therapy for the treatment of Pseudomonas aeruginosa infections in patients with chronic respiratory disease

7QH1 の概要

• エントリーDOI: 10.2210/pdb7qh1/pdb
• 分子名称: Keratinase KP2, ZINC ION, 2-[2-[[5-[3-[bis(2-hydroxyethyl)-methyl-$l^{4}-azanyl]propoxy]-6-methoxy-1,3-benzothiazol-2-yl]methylcarbamoyl]-5,6-bis(fluoranyl)-1,3-dihydroinden-2-yl]ethanoic acid, ... (5 entities in total)
• 機能のキーワード: pseudomonas aeruginosa, respiratory disease, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 135719.08

構造登録者

Leonard, P.M.,Davies, D.,Pallin, T.D. (登録日: 2021-12-10, 公開日: 2022-12-21, 最終更新日: 2024-11-20)

主引用文献

Everett, M.J.,Davies, D.T.,Leiris, S.,Sprynski, N.,Llanos, A.,Castandet, J.M.,Lozano, C.,LaRock, C.N.,LaRock, D.L.,Corsica, G.,Docquier, J.D.,Pallin, T.D.,Cridland, A.,Blench, T.,Zalacain, M.,Lemonnier, M.
Chemical Optimization of Selective Pseudomonas aeruginosa LasB Elastase Inhibitors and Their Impact on LasB-Mediated Activation of IL-1 beta in Cellular and Animal Infection Models.
Acs Infect Dis., 9:270-282, 2023

PubMed Abstract: LasB elastase is a broad-spectrum exoprotease and a key virulence factor of , a major pathogen causing lung damage and inflammation in acute and chronic respiratory infections. Here, we describe the chemical optimization of specific LasB inhibitors with druglike properties and investigate their impact in cellular and animal models of infection. Competitive inhibition of LasB was demonstrated through structural and kinetic studies. LasB inhibition was confirmed with respect to several host target proteins, namely, elastin, IgG, and pro-IL-1β. Furthermore, inhibition of LasB-mediated IL-1β activation was demonstrated in macrophage and mouse lung infection models. In mice, intravenous administration of inhibitors also resulted in reduced bacterial numbers at 24 h. These highly potent, selective, and soluble LasB inhibitors constitute valuable tools to study the proinflammatory impact of LasB in infections and, most importantly, show clear potential for the clinical development of a novel therapy for life-threatening respiratory infections caused by this opportunistic pathogen.

PubMed: 36669138
DOI: 10.1021/acsinfecdis.2c00418

実験手法

X-RAY DIFFRACTION (2.74 Å)