Generalizing a Ligation Site at the N-Glycosylation Sequon for Chemical Synthesis of N-Linked Glycopeptides and Glycoproteins

Dongfang Li; Can Li; Qiushi Chen; Haiyan Zhou; Zhixiang Zhong; Zirong Huang; Han Liu; Xuechen Li

doi:10.1021/jacs.4c09996

Generalizing a Ligation Site at the N-Glycosylation Sequon for Chemical Synthesis of N-Linked Glycopeptides and Glycoproteins

Dongfang Li, Can Li, Qiushi Chen, Haiyan Zhou, Zhixiang Zhong, Zirong Huang, Han Liu^*, Xuechen Li^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

2 Citations (Scopus)

Abstract

Chemical synthesis can generate homogeneous glycoproteins with well-defined and modifiable glycan structures at designated sites. The precision and flexibility of the chemical synthetic approach provide a solution to the heterogeneity problem of glycopeptides/glycoproteins obtained through biological approaches. In this study, we reported that the conserved N-glycosylation sequon (Asn-Xaa-Ser/Thr) of glycoproteins can serve as a general site for performing Ser/Thr ligation to achieve N-linked glycoprotein synthesis. We developed an N + 2 strategy to prepare the corresponding glycopeptide salicylaldehyde esters for Ser/Thr ligation and demonstrated that Ser/Thr ligation at the sequon was not affected by the steric hindrance brought about by the large-sized glycan structures. The effectiveness of this strategy was showcased by the total synthesis of the glycosylated receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. © 2024 American Chemical Society.

Original language	English
Pages (from-to)	29017–29027
Journal	Journal of the American Chemical Society
Volume	146
Issue number	42
Online published	11 Oct 2024
DOIs	https://doi.org/10.1021/jacs.4c09996
Publication status	Published - 23 Oct 2024

Funding

This work was supported by the Research Grants Council of Hong Kong (17312022, 17302621, C7147-20G, AoE/P-705/16), the National Natural Science Foundation of China (22177097), and the Research Grants Council-Senior Research Fellow Scheme (SPFS2324-7S01). We acknowledge the funding support from “Laboratory for Synthetic Chemistry and Chemical Biology” under the Health@InnoHK Program launched by the Innovation and Technology Commission, The Government of Hong Kong Special Administrative Region of the People’s Republic of China.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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title = "Generalizing a Ligation Site at the N-Glycosylation Sequon for Chemical Synthesis of N-Linked Glycopeptides and Glycoproteins",

abstract = "Chemical synthesis can generate homogeneous glycoproteins with well-defined and modifiable glycan structures at designated sites. The precision and flexibility of the chemical synthetic approach provide a solution to the heterogeneity problem of glycopeptides/glycoproteins obtained through biological approaches. In this study, we reported that the conserved N-glycosylation sequon (Asn-Xaa-Ser/Thr) of glycoproteins can serve as a general site for performing Ser/Thr ligation to achieve N-linked glycoprotein synthesis. We developed an N + 2 strategy to prepare the corresponding glycopeptide salicylaldehyde esters for Ser/Thr ligation and demonstrated that Ser/Thr ligation at the sequon was not affected by the steric hindrance brought about by the large-sized glycan structures. The effectiveness of this strategy was showcased by the total synthesis of the glycosylated receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. {\textcopyright} 2024 American Chemical Society.",

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Generalizing a Ligation Site at the N-Glycosylation Sequon for Chemical Synthesis of N-Linked Glycopeptides and Glycoproteins. / Li, Dongfang; Li, Can; Chen, Qiushi et al.
In: Journal of the American Chemical Society, Vol. 146, No. 42, 23.10.2024, p. 29017–29027.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Generalizing a Ligation Site at the N-Glycosylation Sequon for Chemical Synthesis of N-Linked Glycopeptides and Glycoproteins

AU - Li, Dongfang

AU - Li, Can

AU - Chen, Qiushi

AU - Zhou, Haiyan

AU - Zhong, Zhixiang

AU - Huang, Zirong

AU - Liu, Han

AU - Li, Xuechen

PY - 2024/10/23

Y1 - 2024/10/23

N2 - Chemical synthesis can generate homogeneous glycoproteins with well-defined and modifiable glycan structures at designated sites. The precision and flexibility of the chemical synthetic approach provide a solution to the heterogeneity problem of glycopeptides/glycoproteins obtained through biological approaches. In this study, we reported that the conserved N-glycosylation sequon (Asn-Xaa-Ser/Thr) of glycoproteins can serve as a general site for performing Ser/Thr ligation to achieve N-linked glycoprotein synthesis. We developed an N + 2 strategy to prepare the corresponding glycopeptide salicylaldehyde esters for Ser/Thr ligation and demonstrated that Ser/Thr ligation at the sequon was not affected by the steric hindrance brought about by the large-sized glycan structures. The effectiveness of this strategy was showcased by the total synthesis of the glycosylated receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. © 2024 American Chemical Society.

AB - Chemical synthesis can generate homogeneous glycoproteins with well-defined and modifiable glycan structures at designated sites. The precision and flexibility of the chemical synthetic approach provide a solution to the heterogeneity problem of glycopeptides/glycoproteins obtained through biological approaches. In this study, we reported that the conserved N-glycosylation sequon (Asn-Xaa-Ser/Thr) of glycoproteins can serve as a general site for performing Ser/Thr ligation to achieve N-linked glycoprotein synthesis. We developed an N + 2 strategy to prepare the corresponding glycopeptide salicylaldehyde esters for Ser/Thr ligation and demonstrated that Ser/Thr ligation at the sequon was not affected by the steric hindrance brought about by the large-sized glycan structures. The effectiveness of this strategy was showcased by the total synthesis of the glycosylated receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. © 2024 American Chemical Society.

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DO - 10.1021/jacs.4c09996

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Generalizing a Ligation Site at the N-Glycosylation Sequon for Chemical Synthesis of N-Linked Glycopeptides and Glycoproteins

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Funding

UN SDGs

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CRF-ExtU-Lead: Development of Glycopeptide-based Anti SARS-CoV-2 Vaccines

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Generalizing a Ligation Site at the N-Glycosylation Sequon for Chemical Synthesis of N-Linked Glycopeptides and Glycoproteins

Abstract

Funding

UN SDGs

RGC Funding Information

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Other Files and Links

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Projects

CRF-ExtU-Lead: Development of Glycopeptide-based Anti SARS-CoV-2 Vaccines

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