Rational synthesis of a heparan sulfate saccharide that promotes the activity of BMP2
Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved..
Heparan sulfate (HS) is a glycosaminoglycan (GAG) found throughout nature and is involved in a wide range of functions including modulation of cell signalling via sequestration of growth factors. Current consensus is that the specificity of HS motifs for protein binding are individual for each protein. Given the structural complexity of HS the synthesis of libraries of these compounds to probe this is not trivial. Herein we present the synthesis of an HS decamer, the design of which was undertaken rationally from previously published data for HS binding to the growth factor BMP-2. The biological activity of this HS decamer was assessed in vitro, showing that it had the ability to both bind BMP-2 and increase its thermal stability as well as enhancing the bioactivity of BMP-2 in vitro in C2C12 cells. At the same time no undesired anticoagulant effect was observed. This decamer was then analysed in vivo in a rabbit model where higher bone formation, bone mineral density (BMD) and trabecular thickness were observed over an empty defect or collagen implant alone. This indicated that the HS decamer was effective in promoting bone regeneration in vivo.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:333 |
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| Enthalten in: |
Carbohydrate polymers - 333(2024) vom: 01. März, Seite 121979 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shaffer, Karl J [VerfasserIn] |
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| Links: |
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| Themen: |
9050-30-0 |
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| Anmerkungen: |
Date Completed 19.03.2024 Date Revised 19.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.carbpol.2024.121979 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a Heparan sulfate (HS) is a glycosaminoglycan (GAG) found throughout nature and is involved in a wide range of functions including modulation of cell signalling via sequestration of growth factors. Current consensus is that the specificity of HS motifs for protein binding are individual for each protein. Given the structural complexity of HS the synthesis of libraries of these compounds to probe this is not trivial. Herein we present the synthesis of an HS decamer, the design of which was undertaken rationally from previously published data for HS binding to the growth factor BMP-2. The biological activity of this HS decamer was assessed in vitro, showing that it had the ability to both bind BMP-2 and increase its thermal stability as well as enhancing the bioactivity of BMP-2 in vitro in C2C12 cells. At the same time no undesired anticoagulant effect was observed. This decamer was then analysed in vivo in a rabbit model where higher bone formation, bone mineral density (BMD) and trabecular thickness were observed over an empty defect or collagen implant alone. This indicated that the HS decamer was effective in promoting bone regeneration in vivo | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a BMP-2 | |
| 650 | 4 | |a Bone regeneration | |
| 650 | 4 | |a Heparan sulfate | |
| 650 | 4 | |a Rational design | |
| 650 | 7 | |a Heparitin Sulfate |2 NLM | |
| 650 | 7 | |a 9050-30-0 |2 NLM | |
| 650 | 7 | |a Glycosaminoglycans |2 NLM | |
| 650 | 7 | |a Intercellular Signaling Peptides and Proteins |2 NLM | |
| 700 | 1 | |a Smith, Raymond A A |e verfasserin |4 aut | |
| 700 | 1 | |a Daines, Alison M |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Xiaoman |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Xiaohua |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Tuan Chun |e verfasserin |4 aut | |
| 700 | 1 | |a Le, Bach Q |e verfasserin |4 aut | |
| 700 | 1 | |a Schwörer, Ralf |e verfasserin |4 aut | |
| 700 | 1 | |a Hinkley, Simon F R |e verfasserin |4 aut | |
| 700 | 1 | |a Tyler, Peter C |e verfasserin |4 aut | |
| 700 | 1 | |a Nurcombe, Victor |e verfasserin |4 aut | |
| 700 | 1 | |a Cool, Simon M |e verfasserin |4 aut | |
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