Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase
| Autor: | Anders Karlén, Máté Erdélyi, Charles Hedgecock, Andrea Benediktsdottir, Gustav Olanders, Peter Brandt, Edouard Zamaratski, Sherry L. Mowbray, Lu Lu, Sha Cao, Diarmaid Hughes, Natalia Szałaj |
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| Rok vydání: | 2018 |
| Předmět: |
Macrocyclic Compounds
Serine Proteinase Inhibitors Antineoplastic Agents 010402 general chemistry medicine.disease_cause 01 natural sciences Lipopeptides Structure-Activity Relationship Drug Discovery Escherichia coli medicine Humans Cytotoxicity Peptide sequence Cell Proliferation Pharmacology chemistry.chemical_classification Signal peptidase Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Serine Endopeptidases Organic Chemistry Membrane Proteins Esters Hep G2 Cells General Medicine Antimicrobial Boronic Acids Combinatorial chemistry Anti-Bacterial Agents 0104 chemical sciences Enzyme chemistry Drug Screening Assays Antitumor Antibacterial activity Linker |
| Zdroj: | European Journal of Medicinal Chemistry. 157:1346-1360 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2018.08.086 |
| Popis: | Type I signal peptidase, with its vital role in bacterial viability, is a promising but underexploited antibacterial drug target. In the light of steadily increasing rates of antimicrobial resistance, we have developed novel macrocyclic lipopeptides, linking P2 and P1′ by a boronic ester warhead, capable of inhibiting Escherichia coli type I signal peptidase (EcLepB) and exhibiting good antibacterial activity. Structural modifications of the macrocyclic ring, the peptide sequence and the lipophilic tail led us to 14 novel macrocyclic boronic esters. It could be shown that macrocyclization is well tolerated in terms of EcLepB inhibition and antibacterial activity. Among the synthesized macrocycles, potent enzyme inhibitors in the low nanomolar range (e.g. compound 42f, EcLepB IC50 = 29 nM) were identified also showing good antimicrobial activity (e.g. compound 42b, E. coli WT MIC = 16 μg/mL). The unique macrocyclic boronic esters described here were based on previously published linear lipopeptidic EcLepB inhibitors in an attempt to address cytotoxicity and hemolysis. We show herein that structural changes to the macrocyclic ring influence both the cytotoxicity and hemolytic activity suggesting that the P2 to P1' linker provide means for optimizing off-target effects. However, for the present set of compounds we were not able to separate the antibacterial activity and cytotoxic effect. |
| Databáze: | OpenAIRE |
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