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Chemical synthesis of human syndecan-4 glycopeptide bearing O-, N-sulfation and multiple aspartic acids for probing impacts of the glycan chain and the core peptide on biological functions.

ABSTRACT: Proteoglycans are a family of complex glycoproteins with glycosaminoglycan chains such as heparan sulfate (HS) attached to the core protein backbone. Due to the high structural heterogeneity of HS in nature, it is challenging to decipher the respective roles of the HS chain and the core protein on proteoglycan functions. While the sulfation patterns of HS dictate many activities, the core protein can potentially impact HS functions. In order to decipher this, homogeneous proteoglycan glycopeptides are needed. Herein, we report the first successful synthesis of proteoglycan glycopeptides bearing multiple aspartic acids in the core peptide and O- and N-sulfations in the glycan chain, as exemplified by the syndecan-4 glycopeptides. To overcome the high acid sensitivities of sulfates and base sensitivities of the glycopeptide during synthesis, a new synthetic approach has been developed to produce a sulfated glycan chain on a peptide sequence prone to the formation of aspartimide side products. The availability of the structurally well-defined synthetic glycopeptide enabled the investigation of their biological functions including cytokine, growth factor binding and heparanase inhibition. Interestingly, the glycopeptide exhibited context dependent enhancement or decrease of biological activities compared to the peptide or the glycan alone. The results presented herein suggest that besides varying the sulfation patterns of HS, linking the HS chain to core proteins as in proteoglycans may be an additional approach to modulate biological functions of HS in nature.

SUBMITTER: Yang W

PROVIDER: S-EPMC8159385 | biostudies-literature |

REPOSITORIES: biostudies-literature

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