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Design, synthesis, and biological evaluation of novel selective peptide inhibitors of 11β-hydroxysteroid dehydrogenase 1

Boudon, Stephanie and Heidl, Marc and Vuorinen, Anna and Wandeler, Eliane and Campiche, Remo and Odermatt, Alex and Jackson, Eileen. (2018) Design, synthesis, and biological evaluation of novel selective peptide inhibitors of 11β-hydroxysteroid dehydrogenase 1. Bioorganic & medicinal chemistry, 26 (18). pp. 5128-5139.

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Official URL: https://edoc.unibas.ch/68081/

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Abstract

The enzyme 11β-HSD1 plays a crucial role in the tissue-specific regulation of cortisol levels and it has been associated with various diseases. Inhibition of 11β-HSD1 is an attractive intervention strategy and the discovery of novel selective 11β-HSD1 inhibitors is of high relevance. In this study, we identified and evaluated a new series of selective peptide 11β-HSD1 inhibitors with potential for skin care applications. This novel scaffold was designed with the aid of molecular modeling and two previously reported inhibitors. SAR optimization yielded highly active peptides (IC; 50; below 400 nM) that were inactive at 1 µM concentration against structurally related enzymes (11β-HSD2, 17β-HSD1 and 17β-HSD2). The best performing peptides inhibited the conversion of cortisone into cortisol in primary human keratinocytes and the most active compound, 5d, was further shown to reverse cortisone-induced collagen damage in human ex-vivo tissue.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1464-3391
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:15 Apr 2020 16:30
Deposited On:15 Apr 2020 16:30

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