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Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors
Rhomboid proteases are intramembrane serine proteases, which are involved in a wide variety of biological processes and have been implied in various human diseases. Recently, peptidyl α-ketoamides have been reported as rhomboid inhibitors with high potency and selectivity – owing to their interactio...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8694341/ https://www.ncbi.nlm.nih.gov/pubmed/35424368 http://dx.doi.org/10.1039/d0ra10614c |
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author | Van Kersavond, Tim Konopatzki, Raphael van der Plassche, Merel A. T. Yang, Jian Verhelst, Steven H. L. |
author_facet | Van Kersavond, Tim Konopatzki, Raphael van der Plassche, Merel A. T. Yang, Jian Verhelst, Steven H. L. |
author_sort | Van Kersavond, Tim |
collection | PubMed |
description | Rhomboid proteases are intramembrane serine proteases, which are involved in a wide variety of biological processes and have been implied in various human diseases. Recently, peptidyl α-ketoamides have been reported as rhomboid inhibitors with high potency and selectivity – owing to their interaction with both the primed and non-primed site of the target protease. However, their synthesis has been performed by solution phase chemistry. Here, we report a solid phase strategy towards ketoamides as rhomboid protease inhibitors, allowing rapid synthesis and optimization. We found that the primed site binding part of inhibitors is crucial for potency. |
format | Online Article Text |
id | pubmed-8694341 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-86943412022-04-13 Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors Van Kersavond, Tim Konopatzki, Raphael van der Plassche, Merel A. T. Yang, Jian Verhelst, Steven H. L. RSC Adv Chemistry Rhomboid proteases are intramembrane serine proteases, which are involved in a wide variety of biological processes and have been implied in various human diseases. Recently, peptidyl α-ketoamides have been reported as rhomboid inhibitors with high potency and selectivity – owing to their interaction with both the primed and non-primed site of the target protease. However, their synthesis has been performed by solution phase chemistry. Here, we report a solid phase strategy towards ketoamides as rhomboid protease inhibitors, allowing rapid synthesis and optimization. We found that the primed site binding part of inhibitors is crucial for potency. The Royal Society of Chemistry 2021-01-20 /pmc/articles/PMC8694341/ /pubmed/35424368 http://dx.doi.org/10.1039/d0ra10614c Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Van Kersavond, Tim Konopatzki, Raphael van der Plassche, Merel A. T. Yang, Jian Verhelst, Steven H. L. Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors |
title | Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors |
title_full | Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors |
title_fullStr | Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors |
title_full_unstemmed | Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors |
title_short | Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors |
title_sort | rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8694341/ https://www.ncbi.nlm.nih.gov/pubmed/35424368 http://dx.doi.org/10.1039/d0ra10614c |
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