Cargando…
Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide
Selective modification of native proteins in live cells is one of the central challenges in recent chemical biology. As a unique bioorthogonal approach, ligand-directed chemistry recently emerged, but the slow kinetics limits its scope. Here we successfully overcome this obstacle using N-acyl-N-alky...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951806/ https://www.ncbi.nlm.nih.gov/pubmed/29760386 http://dx.doi.org/10.1038/s41467-018-04343-0 |
_version_ | 1783323072449740800 |
---|---|
author | Tamura, Tomonori Ueda, Tsuyoshi Goto, Taiki Tsukidate, Taku Shapira, Yonatan Nishikawa, Yuki Fujisawa, Alma Hamachi, Itaru |
author_facet | Tamura, Tomonori Ueda, Tsuyoshi Goto, Taiki Tsukidate, Taku Shapira, Yonatan Nishikawa, Yuki Fujisawa, Alma Hamachi, Itaru |
author_sort | Tamura, Tomonori |
collection | PubMed |
description | Selective modification of native proteins in live cells is one of the central challenges in recent chemical biology. As a unique bioorthogonal approach, ligand-directed chemistry recently emerged, but the slow kinetics limits its scope. Here we successfully overcome this obstacle using N-acyl-N-alkyl sulfonamide as a reactive group. Quantitative kinetic analyses reveal that ligand-directed N-acyl-N-alkyl sulfonamide chemistry allows for rapid modification of a lysine residue proximal to the ligand binding site of a target protein, with a rate constant of ~10(4) M(−1) s(−1), comparable to the fastest bioorthogonal chemistry. Despite some off-target reactions, this method can selectively label both intracellular and membrane-bound endogenous proteins. Moreover, the unique reactivity of N-acyl-N-alkyl sulfonamide enables the rational design of a lysine-targeted covalent inhibitor that shows durable suppression of the activity of Hsp90 in cancer cells. This work provides possibilities to extend the covalent inhibition approach that is currently being reassessed in drug discovery. |
format | Online Article Text |
id | pubmed-5951806 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59518062018-05-16 Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide Tamura, Tomonori Ueda, Tsuyoshi Goto, Taiki Tsukidate, Taku Shapira, Yonatan Nishikawa, Yuki Fujisawa, Alma Hamachi, Itaru Nat Commun Article Selective modification of native proteins in live cells is one of the central challenges in recent chemical biology. As a unique bioorthogonal approach, ligand-directed chemistry recently emerged, but the slow kinetics limits its scope. Here we successfully overcome this obstacle using N-acyl-N-alkyl sulfonamide as a reactive group. Quantitative kinetic analyses reveal that ligand-directed N-acyl-N-alkyl sulfonamide chemistry allows for rapid modification of a lysine residue proximal to the ligand binding site of a target protein, with a rate constant of ~10(4) M(−1) s(−1), comparable to the fastest bioorthogonal chemistry. Despite some off-target reactions, this method can selectively label both intracellular and membrane-bound endogenous proteins. Moreover, the unique reactivity of N-acyl-N-alkyl sulfonamide enables the rational design of a lysine-targeted covalent inhibitor that shows durable suppression of the activity of Hsp90 in cancer cells. This work provides possibilities to extend the covalent inhibition approach that is currently being reassessed in drug discovery. Nature Publishing Group UK 2018-05-14 /pmc/articles/PMC5951806/ /pubmed/29760386 http://dx.doi.org/10.1038/s41467-018-04343-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Tamura, Tomonori Ueda, Tsuyoshi Goto, Taiki Tsukidate, Taku Shapira, Yonatan Nishikawa, Yuki Fujisawa, Alma Hamachi, Itaru Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide |
title | Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide |
title_full | Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide |
title_fullStr | Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide |
title_full_unstemmed | Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide |
title_short | Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide |
title_sort | rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed n-acyl-n-alkyl sulfonamide |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951806/ https://www.ncbi.nlm.nih.gov/pubmed/29760386 http://dx.doi.org/10.1038/s41467-018-04343-0 |
work_keys_str_mv | AT tamuratomonori rapidlabellingandcovalentinhibitionofintracellularnativeproteinsusingliganddirectednacylnalkylsulfonamide AT uedatsuyoshi rapidlabellingandcovalentinhibitionofintracellularnativeproteinsusingliganddirectednacylnalkylsulfonamide AT gototaiki rapidlabellingandcovalentinhibitionofintracellularnativeproteinsusingliganddirectednacylnalkylsulfonamide AT tsukidatetaku rapidlabellingandcovalentinhibitionofintracellularnativeproteinsusingliganddirectednacylnalkylsulfonamide AT shapirayonatan rapidlabellingandcovalentinhibitionofintracellularnativeproteinsusingliganddirectednacylnalkylsulfonamide AT nishikawayuki rapidlabellingandcovalentinhibitionofintracellularnativeproteinsusingliganddirectednacylnalkylsulfonamide AT fujisawaalma rapidlabellingandcovalentinhibitionofintracellularnativeproteinsusingliganddirectednacylnalkylsulfonamide AT hamachiitaru rapidlabellingandcovalentinhibitionofintracellularnativeproteinsusingliganddirectednacylnalkylsulfonamide |