7qh1

From Proteopedia

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

Structural highlights

7qh1 is a 4 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.74Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ELAS_PSEAE Cleaves elastin, collagen, IgG, and several complement components. Involved in the pathogenesis of P.aeruginosa infections.

Publication Abstract from PubMed

LasB elastase is a broad-spectrum exoprotease and a key virulence factor of Pseudomonas aeruginosa, 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 P. aeruginosa infection. Competitive inhibition of LasB was demonstrated through structural and kinetic studies. In vitro LasB inhibition was confirmed with respect to several host target proteins, namely, elastin, IgG, and pro-IL-1beta. Furthermore, inhibition of LasB-mediated IL-1beta 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 P. aeruginosa 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.

Chemical Optimization of Selective Pseudomonas aeruginosa LasB Elastase Inhibitors and Their Impact on LasB-Mediated Activation of IL-1beta in Cellular and Animal Infection Models.,Everett MJ, Davies DT, Leiris S, Sprynski N, Llanos A, Castandet JM, Lozano C, LaRock CN, LaRock DL, Corsica G, Docquier JD, Pallin TD, Cridland A, Blench T, Zalacain M, Lemonnier M ACS Infect Dis. 2023 Feb 10;9(2):270-282. doi: 10.1021/acsinfecdis.2c00418. Epub , 2023 Jan 20. PMID:36669138^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Everett MJ, Davies DT, Leiris S, Sprynski N, Llanos A, Castandet JM, Lozano C, LaRock CN, LaRock DL, Corsica G, Docquier JD, Pallin TD, 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-1β in Cellular and Animal Infection Models. ACS Infect Dis. 2023 Feb 10;9(2):270-282. PMID:36669138 doi:10.1021/acsinfecdis.2c00418