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Published on: June 30, 2016
Virtual Screening Approach to Identifying a Novel and Tractable Series of Pseudomonas aeruginosa Elastase Inhibitors
Simon Leiris1, David T Davies1, Nicolas Sprynski1
1Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France.
Abstract:
Novel therapies are required to treat chronic bacterial infections in cystic fibrosis (CF) sufferers. The most common pathogen responsible for these infections is Pseudomonas aeruginosa, which persists within the lungs of CF sufferers despite intensive antibiotic treatment. P. aeruginosa elastase (also known as LasB or pseudolysin) is a key virulence determinant that contributes to the pathogenesis and persistence of P. aeruginosa infections in CF patients. The crucial role of LasB in pseudomonal virulence makes it a good target for the development of an adjuvant drug for CF treatment. Herein we discuss the discovery of a new series of LasB inhibitors by virtual screening and computer assisted drug design (CADD) and their optimization leading to compounds 29 and 39 (K i = 0.16 μM and 0.12 μM, respectively).
Insights
New therapies are needed for chronic bacterial infections in cystic fibrosis (CF) patients. Researchers discovered novel inhibitors targeting Pseudomonas aeruginosa elastase (LasB), a key factor in persistent lung infections, offering a potential new treatment strategy.
Area of Science:
- Biochemistry
- Microbiology
- Drug Discovery
Background:
- Chronic bacterial infections, particularly by *Pseudomonas aeruginosa*, pose a significant challenge in cystic fibrosis (CF) treatment.
- *P. aeruginosa* elastase (LasB) is a critical virulence factor contributing to the persistence of these infections in CF patients' lungs.
- Targeting LasB presents a promising strategy for developing novel adjuvant therapies for CF.
Purpose of the Study:
- To discover and develop new inhibitors of *P. aeruginosa* elastase (LasB).
- To identify potential therapeutic agents to combat chronic *P. aeruginosa* infections in cystic fibrosis.
Main Methods:
- Utilized virtual screening and computer-assisted drug design (CADD) to identify potential LasB inhibitors.
- Optimized lead compounds through medicinal chemistry efforts.
Main Results:
- Discovered a novel series of LasB inhibitors.
- Identified optimized compounds 29 and 39 with potent inhibitory activity (Ki = 0.16 μM and 0.12 μM, respectively).
Conclusions:
- The identified LasB inhibitors represent promising candidates for further development as adjuvant therapies for CF.
- Targeting LasB is a viable strategy to address persistent *P. aeruginosa* infections in cystic fibrosis.
