2. Academic Validation
  3. Multiparameter Optimization of Pseudomonas aeruginosa Elastase Inhibitors for Systemic Administration

Multiparameter Optimization of Pseudomonas aeruginosa Elastase Inhibitors for Systemic Administration

  • J Med Chem. 2026 Feb 26;69(4):4160-4186. doi: 10.1021/acs.jmedchem.5c02788.
Ahmed S Abdelsamie 1 2,  Jelena Konstantinović 1 2,  Andreas M Kany 1 2 3,  Christian Schütz 1 2,  Dominik Kolling 1 2 4 5,  Samira Speicher 1 2,  Andreas Klein 1 2,  Roya Shafiei 1 2,  Mélodie Bouté 6,  Katharina Mundry 4,  Yu Mi Park 1 2,  Brigitta Loretz 1 2,  Rolf Müller 1 2 3 5 7,  Jean-Michel Sallenave 6 8,  Claus-Michael Lehr 1 2 5,  Jesko Koehnke 4,  Katharina Rox 3 9,  Jörg Haupenthal 1 2 3,  Anna K H Hirsch 1 2 3 5 7
Affiliations

Affiliations

  • 1 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany.
  • 2 PharmaScienceHub, Saarbrücken 66123, Germany.
  • 3 Deutsches Zentrum für Infektionsforschung (DZIF) e.V., Partner site Braunschweig-Hannover, Braunschweig 38124, Germany.
  • 4 Institute for Food Chemistry, Hannover 30167, Germany.
  • 5 Department of Pharmacy, Saarbrücken 66123, Germany.
  • 6 Laboratoire d'Excellence Inflamex, Institut National de la Santé et de la Recherche Medicale U1152, Physiopathologie et Épidémiologie des Maladies Respiratoires, Université Paris-Cité, Paris 75006, France.
  • 7 Helmholtz International Lab for Anti-infectives, Saarbrücken 66123, Germany.
  • 8 INSERM U1149, Centre de Recherche sur l'Inflammation, Hôpital Bichat, Université Paris-Cité, 16 rue Henri Huchard, Paris 75018, France.
  • 9 Department of Chemical Biology (CBIO), Helmholtz Centre for Infection Research (HZI), Braunschweig 38124, Germany.
PMID: 41642952 DOI: 10.1021/acs.jmedchem.5c02788
Abstract

Targeting the extracellular protease Elastase (LasB) of the high-priority pathogen Pseudomonas aeruginosa is a promising strategy to develop second-generation, narrow-spectrum Antibiotics with a novel mode of action. P. aeruginosa is responsible for a variety of infections, particularly of the lung. Herein, we report the structure-based optimization of a previously reported potent and selective phosphonate-based LasB inhibitor scaffold. Having improved the activity while maintaining high selectivity and favorable ADMET properties, we also demonstrate, for the first time within this scaffold, that intravenous administration leads to favorable lung retention. We could rationally align this with in vitro plasma protein binding. We further observed a link between physicochemical properties like logD7.4 and protein binding, including surfactant proteins that can impair compound activity in the lung. This multiparameter optimization paves the way for the exploration of additional indications requiring systemic treatment, such as hospital-acquired or ventilator-associated pneumonia.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z