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Obstacles and solutions for chemical synthesis of syndecan-3 (53-62) glycopeptides with two heparan sulfate chains.

ABSTRACT: Proteoglycans play critical roles in many biological events. Due to their structural complexities, strategies towards synthesis of this class of glycopeptides bearing well-defined glycan chains are urgently needed. In this work, we give the full account of the synthesis of syndecan-3 glycopeptide (53-62) containing two different heparan sulfate chains. For assembly of glycans, a convergent 3+2+3 approach was developed producing two different octasaccharide amino acid cassettes, which were utilized towards syndecan-3 glycopeptides. The glycopeptides presented many obstacles for post-glycosylation manipulation, peptide elongation, and deprotection. Following screening of multiple synthetic sequences, a successful strategy was finally established by constructing partially deprotected single glycan chain containing glycopeptides first, followed by coupling of the glycan-bearing fragments and cleavage of the acyl protecting groups.

SUBMITTER: Yang W

PROVIDER: S-EPMC5110403 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Obstacles and solutions for chemical synthesis of syndecan-3 (53-62) glycopeptides with two heparan sulfate chains.

Yang Weizhun W Yoshida Keisuke K Yang Bo B Huang Xuefei X

Carbohydrate research 20161020

Proteoglycans play critical roles in many biological events. Due to their structural complexities, strategies towards synthesis of this class of glycopeptides bearing well-defined glycan chains are urgently needed. In this work, we give the full account of the synthesis of syndecan-3 glycopeptide (53-62) containing two different heparan sulfate chains. For assembly of glycans, a convergent 3+2+3 approach was developed producing two different octasaccharide amino acid cassettes, which were utiliz ...[more]

PMID: 27810711

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Project description:Expression of the cell surface proteoglycan syndecan-1 (Sdc1) is frequently induced in stromal fibroblasts of invasive breast carcinomas. We have recently identified a correlation between stromal Sdc1 expression and extracellular matrix (ECM) fiber alignment, both in vitro and in vivo. ECMs derived from Sdc1-positive human mammary fibroblasts (HMF) showed an aligned fiber architecture, which contrasted markedly with the more random fiber arrangement in the ECM produced by Sdc1-negative HMFs. We further demonstrated that aligned fiber architecture promotes the directional migration and invasion of breast carcinoma cells. To decipher the molecular mechanisms governing the formation of an aligned, invasion-permissive ECM, a series of Sdc1 mutants was introduced into HMF. We found that both the ectodomain and heparan sulfate chains of Sdc1 were required for full activity of Sdc1 in regulating ECM alignment, while transmembrane and cytoplasmic domains were dispensable. Sdc1 regulates the activities of several integrins via its ectodomain. Integrins are key players in the assembly of fibronectin-rich ECM. In addition, integrins are capable of regulating cell morphology and cell shape and orientation may affect ECM architecture. Therefore, we investigated the role of integrins in Sdc1-mediated ECM fiber alignment. Sdc1-overexpressing HMF gained an enhanced spindle-shaped morphology when cultured in an overconfluent state under conditions permissive for ECM production, which was partially reversed by siRNA-mediated silencing of ?3 integrin expression. Moreover, suppression of ?v?3 integrin activity by a function-blocking antibody or ?3 knockdown largely abolished the aligned ECM fiber architecture and consequently the invasion-permissive properties of the ECM induced by Sdc1. The results suggest that Sdc1 may modulate fibronectin fibrillogenesis and/or alter cell morphology during ECM production through ?v?3 integrin, thereby mediating ECM fiber alignment. Understanding the mechanisms governing ECM organization may lead to the development of novel stroma-targeted therapy for breast cancer, aiming at converting an invasion-permissive to an invasion-restrictive microenvironment.

Dataset Information

Obstacles and solutions for chemical synthesis of syndecan-3 (53-62) glycopeptides with two heparan sulfate chains.

Publications

Obstacles and solutions for chemical synthesis of syndecan-3 (53-62) glycopeptides with two heparan sulfate chains.

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