8CC4

LasB bound to phosphonic acid based inhibitor

8CC4 の概要

• エントリーDOI: 10.2210/pdb8cc4/pdb
• 分子名称: Elastase, CALCIUM ION, [(2~{R})-4-methyl-1-oxidanylidene-1-[[4-(trifluoromethyl)phenyl]amino]pentan-2-yl]phosphonic acid, ... (5 entities in total)
• 機能のキーワード: lasb, (4-methyl-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)pentan-2-yl)phosphonic acid inhibitor complex, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67240.53

構造登録者

Mueller, R.,Sikandar, A. (登録日: 2023-01-26, 公開日: 2023-12-06, 最終更新日: 2024-11-20)

主引用文献

Konstantinovic, J.,Kany, A.M.,Alhayek, A.,Abdelsamie, A.S.,Sikandar, A.,Voos, K.,Yao, Y.,Andreas, A.,Shafiei, R.,Loretz, B.,Schonauer, E.,Bals, R.,Brandstetter, H.,Hartmann, R.W.,Ducho, C.,Lehr, C.M.,Beisswenger, C.,Muller, R.,Rox, K.,Haupenthal, J.,Hirsch, A.K.H.
Inhibitors of the Elastase LasB for the Treatment of Pseudomonas aeruginosa Lung Infections.
Acs Cent.Sci., 9:2205-2215, 2023

PubMed Abstract: Infections caused by the Gram-negative pathogen are emerging worldwide as a major threat to human health. Conventional antibiotic monotherapy suffers from rapid resistance development, underlining urgent need for novel treatment concepts. Here, we report on a nontraditional approach to combat -derived infections by targeting its main virulence factor, the elastase LasB. We discovered a new chemical class of phosphonates with an outstanding ADMET and PK profile, auspicious activity both and . We established the mode of action through a cocrystal structure of our lead compound with LasB and in several and models. The proof of concept of a combination of our pathoblocker with levofloxacin in a murine neutropenic lung infection model and the reduction of LasB protein levels in blood as a proof of target engagement demonstrate the great potential for use as an adjunctive treatment of lung infections in humans.

PubMed: 38161367
DOI: 10.1021/acscentsci.3c01102

実験手法

X-RAY DIFFRACTION (2.7 Å)