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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...

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Autores principales: Van Kersavond, Tim, Konopatzki, Raphael, van der Plassche, Merel A. T., Yang, Jian, Verhelst, Steven H. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2021
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.
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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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