7QH1
Discovery and development of a novel inhaled antivirulence therapy for the treatment of Pseudomonas aeruginosa infections in patients with chronic respiratory disease
Summary for 7QH1
| Entry DOI | 10.2210/pdb7qh1/pdb |
| Descriptor | 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) |
| Functional Keywords | pseudomonas aeruginosa, respiratory disease, hydrolase |
| Biological source | Pseudomonas aeruginosa |
| Total number of polymer chains | 4 |
| Total formula weight | 135719.08 |
| Authors | Leonard, P.M.,Davies, D.,Pallin, T.D. (deposition date: 2021-12-10, release date: 2022-12-21, Last modification date: 2024-11-20) |
| Primary citation | 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 Cited by 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: 36669138DOI: 10.1021/acsinfecdis.2c00418 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.74 Å) |
Structure validation
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