8CC4

LasB bound to phosphonic acid based inhibitor

Summary for 8CC4

• Entry DOI: 10.2210/pdb8cc4/pdb
• Descriptor: Elastase, CALCIUM ION, [(2~{R})-4-methyl-1-oxidanylidene-1-[[4-(trifluoromethyl)phenyl]amino]pentan-2-yl]phosphonic acid, ... (5 entities in total)
• Functional Keywords: lasb, (4-methyl-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)pentan-2-yl)phosphonic acid inhibitor complex, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 67240.53

Authors

Mueller, R.,Sikandar, A. (deposition date: 2023-01-26, release date: 2023-12-06, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.7 Å)