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Discovery of rare sulfated N-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines

Achieving selective inhibition of chemokines with structurally well-defined heparan sulfate (HS) oligosaccharides can provide important insights into cancer cell migration and metastasis. However, HS is highly heterogeneous in chemical composition, which limits its therapeutic use. Here, we report t...

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Autores principales: Jain, Prashant, Shanthamurthy, Chethan D., Leviatan Ben-Arye, Shani, Woods, Robert J., Kikkeri, Raghavendra, Padler-Karavani, Vered
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025211/
https://www.ncbi.nlm.nih.gov/pubmed/33889380
http://dx.doi.org/10.1039/d0sc05862a
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author Jain, Prashant
Shanthamurthy, Chethan D.
Leviatan Ben-Arye, Shani
Woods, Robert J.
Kikkeri, Raghavendra
Padler-Karavani, Vered
author_facet Jain, Prashant
Shanthamurthy, Chethan D.
Leviatan Ben-Arye, Shani
Woods, Robert J.
Kikkeri, Raghavendra
Padler-Karavani, Vered
author_sort Jain, Prashant
collection PubMed
description Achieving selective inhibition of chemokines with structurally well-defined heparan sulfate (HS) oligosaccharides can provide important insights into cancer cell migration and metastasis. However, HS is highly heterogeneous in chemical composition, which limits its therapeutic use. Here, we report the rational design and synthesis of N-unsubstituted (NU) and N-acetylated (NA) heparan sulfate tetrasaccharides that selectively inhibit structurally homologous chemokines. HS analogs were produced by divergent synthesis, where fully protected HS tetrasaccharide precursor was subjected to selective deprotection and regioselectively O-sulfated, and O-phosphorylated to obtain 13 novel HS tetrasaccharides. HS microarray and SPR analysis with a wide range of chemokines revealed the structural significance of sulfation patterns and NU domain in chemokine activities for the first time. Particularly, HT-3,6S-NH revealed selective recognition by CCL2 chemokine. Further systematic interrogation of the role of HT-3,6S-NH in cancer demonstrated an effective blockade of CCL2 and its receptor CCR2 interactions, thereby impairing cancer cell proliferation, migration and invasion, a step towards designing novel drug molecules.
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spelling pubmed-80252112021-04-21 Discovery of rare sulfated N-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines Jain, Prashant Shanthamurthy, Chethan D. Leviatan Ben-Arye, Shani Woods, Robert J. Kikkeri, Raghavendra Padler-Karavani, Vered Chem Sci Chemistry Achieving selective inhibition of chemokines with structurally well-defined heparan sulfate (HS) oligosaccharides can provide important insights into cancer cell migration and metastasis. However, HS is highly heterogeneous in chemical composition, which limits its therapeutic use. Here, we report the rational design and synthesis of N-unsubstituted (NU) and N-acetylated (NA) heparan sulfate tetrasaccharides that selectively inhibit structurally homologous chemokines. HS analogs were produced by divergent synthesis, where fully protected HS tetrasaccharide precursor was subjected to selective deprotection and regioselectively O-sulfated, and O-phosphorylated to obtain 13 novel HS tetrasaccharides. HS microarray and SPR analysis with a wide range of chemokines revealed the structural significance of sulfation patterns and NU domain in chemokine activities for the first time. Particularly, HT-3,6S-NH revealed selective recognition by CCL2 chemokine. Further systematic interrogation of the role of HT-3,6S-NH in cancer demonstrated an effective blockade of CCL2 and its receptor CCR2 interactions, thereby impairing cancer cell proliferation, migration and invasion, a step towards designing novel drug molecules. Royal Society of Chemistry 2021-01-28 /pmc/articles/PMC8025211/ /pubmed/33889380 http://dx.doi.org/10.1039/d0sc05862a Text en This journal is © The Royal Society of Chemistry 2021 http://creativecommons.org/licenses/by-nc/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported Licence (CC BY-NC 3.0)
spellingShingle Chemistry
Jain, Prashant
Shanthamurthy, Chethan D.
Leviatan Ben-Arye, Shani
Woods, Robert J.
Kikkeri, Raghavendra
Padler-Karavani, Vered
Discovery of rare sulfated N-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines
title Discovery of rare sulfated N-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines
title_full Discovery of rare sulfated N-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines
title_fullStr Discovery of rare sulfated N-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines
title_full_unstemmed Discovery of rare sulfated N-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines
title_short Discovery of rare sulfated N-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines
title_sort discovery of rare sulfated n-unsubstituted glucosamine based heparan sulfate analogs selectively activating chemokines
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025211/
https://www.ncbi.nlm.nih.gov/pubmed/33889380
http://dx.doi.org/10.1039/d0sc05862a
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