Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein
| Autor: | Marie-Agnès Lacour, Jean Martinez, Fabien Rodier, Vincent Lisowski, Youness Touati-Jallabe, Marine Peuchmaur, Frédéric Checler, Jean-François Hernandez, Jean Sevalle |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Proteases
Stereochemistry Clinical Biochemistry Pharmaceutical Science Transfection Biochemistry Serine Amyloid beta-Protein Precursor chemistry.chemical_compound Drug Discovery Humans Molecular Biology Gamma secretase Serine protease Amyloid beta-Peptides biology Chemistry Organic Chemistry P3 peptide Serine hydrolase Boronic Acids Isocoumarin HEK293 Cells Isocoumarins Alpha secretase biology.protein Molecular Medicine Amyloid Precursor Protein Secretases Serine Proteases |
| Zdroj: | Bioorganic & Medicinal Chemistry. 21:1018-1029 |
| ISSN: | 0968-0896 |
| Popis: | The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid β-peptide (Aβ) by Amyloid-β Precursor Protein (APP) expressing HEK293 cells by affecting the γ-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent γ-secretase complex but more likely interfere with an upstream target involved in γ-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for Aβ-lowering activity and supported the involvement of a serine protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC(50) between 10 and 30μM. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular Aβ production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives. |
| Databáze: | OpenAIRE |
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