A new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization.

Rhomboids are intramembrane serine proteases that play diverse biological roles, including some that are of potential therapeutical relevance. Up to date, rhomboid inhibitor assays are based on protein substrate cleavage. Although rhomboids have an overlapping substrate specificity, substrates canno...

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Autores principales:	Eliane V Wolf, Annett Zeißler, Oliver Vosyka, Evelyn Zeiler, Stephan Sieber, Steven H L Verhelst
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/70b1cebe224a4393822bbb3f7abd2254
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id	oai:doaj.org-article:70b1cebe224a4393822bbb3f7abd2254
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spelling	oai:doaj.org-article:70b1cebe224a4393822bbb3f7abd22542021-11-18T08:58:26ZA new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization.1932-620310.1371/journal.pone.0072307https://doaj.org/article/70b1cebe224a4393822bbb3f7abd22542013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23991088/?tool=EBIhttps://doaj.org/toc/1932-6203Rhomboids are intramembrane serine proteases that play diverse biological roles, including some that are of potential therapeutical relevance. Up to date, rhomboid inhibitor assays are based on protein substrate cleavage. Although rhomboids have an overlapping substrate specificity, substrates cannot be used universally. To overcome the need for substrates, we developed a screening assay using fluorescence polarization activity-based protein profiling (FluoPol ABPP) that is compatible with membrane proteases. With FluoPol ABPP, we identified new inhibitors for the E. coli rhomboid GlpG. Among these was a structural class that has not yet been reported as rhomboid inhibitors: β-lactones. They form covalent and irreversible complexes with the active site serine of GlpG. The presence of alkyne handles on the β-lactones also allowed activity-based labeling. Overall, these molecules represent a new scaffold for future inhibitor and activity-based probe development, whereas the assay will allow inhibitor screening of ill-characterized membrane proteases.Eliane V WolfAnnett ZeißlerOliver VosykaEvelyn ZeilerStephan SieberSteven H L VerhelstPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e72307 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Eliane V Wolf Annett Zeißler Oliver Vosyka Evelyn Zeiler Stephan Sieber Steven H L Verhelst A new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization.
description	Rhomboids are intramembrane serine proteases that play diverse biological roles, including some that are of potential therapeutical relevance. Up to date, rhomboid inhibitor assays are based on protein substrate cleavage. Although rhomboids have an overlapping substrate specificity, substrates cannot be used universally. To overcome the need for substrates, we developed a screening assay using fluorescence polarization activity-based protein profiling (FluoPol ABPP) that is compatible with membrane proteases. With FluoPol ABPP, we identified new inhibitors for the E. coli rhomboid GlpG. Among these was a structural class that has not yet been reported as rhomboid inhibitors: β-lactones. They form covalent and irreversible complexes with the active site serine of GlpG. The presence of alkyne handles on the β-lactones also allowed activity-based labeling. Overall, these molecules represent a new scaffold for future inhibitor and activity-based probe development, whereas the assay will allow inhibitor screening of ill-characterized membrane proteases.
format	article
author	Eliane V Wolf Annett Zeißler Oliver Vosyka Evelyn Zeiler Stephan Sieber Steven H L Verhelst
author_facet	Eliane V Wolf Annett Zeißler Oliver Vosyka Evelyn Zeiler Stephan Sieber Steven H L Verhelst
author_sort	Eliane V Wolf
title	A new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization.
title_short	A new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization.
title_full	A new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization.
title_fullStr	A new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization.
title_full_unstemmed	A new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization.
title_sort	new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/70b1cebe224a4393822bbb3f7abd2254
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A new class of rhomboid protease inhibitors discovered by activity-based fluorescence polarization.

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