ArticleAngewandte Chemie (International ed. in English)2022
Substrate-Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors.
Article in Angewandte Chemie (International ed. in English), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 22 citations in OpenAlex.
- Multiparameter Optimization ofJournal of medicinal chemistry · 2026Article
- Review
- Dipeptidic Phosphonates: Potent Inhibitors of Pseudomonas aeruginosa Elastase B Showing Efficacy in a Murine Keratitis Model.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Ocular surface microbiota alterations in patients with pterygium.Frontiers in cellular and infection microbiology · 2025Article
- Dual inhibitors ofChemical science · 2024Article
- DNA encoded peptide library for SARS-CoV-2 3CL protease covalent inhibitor discovery and profiling.RSC chemical biology · 2024Article
- Inhibitors of the Elastase LasB for the Treatment ofACS central science · 2023Article
- 30th Annual GPPharmaceuticals (Basel, Switzerland) · 2023Article
- Fighting antibiotic resistance-strategies and (pre)clinical developments to find new antibacterials.EMBO reports · 2023Review
- A Formylglycine-Peptide for the Site-Directed Identification of Phosphotyrosine-Mimetic Fragments.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- The Structures and Binding Modes of Small-Molecule Inhibitors ofAntibiotics (Basel, Switzerland) · 2022Review
- Structure-Based Design of α-Substituted Mercaptoacetamides as Inhibitors of the Virulence Factor LasB fromACS infectious diseases · 2022Article
- Substrate-Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors.Angewandte Chemie (International ed. in English) · 2022Article
- Using Structure-guided Fragment-Based Drug Discovery to TargetFrontiers in molecular biosciences · 2022Review
- Virulence Factors ofFrontiers in cellular and infection microbiology · 2022Review
- Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases.Molecules (Basel, Switzerland) · 2021Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a sub-micromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.